WO2006121831A2 - Hiv integrase inhibitors - Google Patents
Hiv integrase inhibitors Download PDFInfo
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- WO2006121831A2 WO2006121831A2 PCT/US2006/017369 US2006017369W WO2006121831A2 WO 2006121831 A2 WO2006121831 A2 WO 2006121831A2 US 2006017369 W US2006017369 W US 2006017369W WO 2006121831 A2 WO2006121831 A2 WO 2006121831A2
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- Prior art keywords
- alkyl
- chloro
- naphthyridine
- fluorobenzyl
- alkylene
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- 0 *C(C(*=C1N(*)CC(*)(*)C(*)(*)C2(*)*)C(C(C3=O)=C4O)=C1N2C4=O)N3I Chemical compound *C(C(*=C1N(*)CC(*)(*)C(*)(*)C2(*)*)C(C(C3=O)=C4O)=C1N2C4=O)N3I 0.000 description 4
- IETZOOBCERHNOP-UHFFFAOYSA-N CC(C)(C(N(CCOC(C)=O)C1=C(CCN(Cc(cc2Cl)ccc2F)C2=O)C2=C2O)=O)N1C2=O Chemical compound CC(C)(C(N(CCOC(C)=O)C1=C(CCN(Cc(cc2Cl)ccc2F)C2=O)C2=C2O)=O)N1C2=O IETZOOBCERHNOP-UHFFFAOYSA-N 0.000 description 1
- UJDJUYUHKGRJPC-UHFFFAOYSA-N OC(C(N(CCOC1=O)C1=C1CCN2Cc(cc3Cl)ccc3F)=O)=C1C2=O Chemical compound OC(C(N(CCOC1=O)C1=C1CCN2Cc(cc3Cl)ccc3F)=O)=C1C2=O UJDJUYUHKGRJPC-UHFFFAOYSA-N 0.000 description 1
- IWNQGAMTNCUPIS-UHFFFAOYSA-N OCCN(CCCCN(C1=O)C2=C(CCN(Cc(cc3Cl)ccc3F)C3=O)C3=C1O)C2=O Chemical compound OCCN(CCCCN(C1=O)C2=C(CCN(Cc(cc3Cl)ccc3F)C3=O)C3=C1O)C2=O IWNQGAMTNCUPIS-UHFFFAOYSA-N 0.000 description 1
Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
Definitions
- the present invention is directed to tricyclic analogs of hydroxy polyhydro-2,6- naphthyridine dione compounds and pharmaceutically acceptable salts thereof, their synthesis, and their use as inhibitors of the HIV integrase en2yme.
- the compounds and pharmaceutically acceptable salts thereof of the present invention are useful for preventing or treating infection by HTV and for preventing or treating or delaying the onset of AIDS.
- a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
- HIV human immunodeficiency virus
- HTV-2 type-2 virus
- retrovirus replication is the insertion by virally-encoded integrase of ⁇ proviral DNA into the host cell genome, a required step in HTV 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 HTV 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 HTV 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 en2ymes have been shown to be essential for the replication of HTV.
- antiviral compounds which act as inhibitors of HTV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhbitors such as indinavir and nelf ⁇ navir.
- the compounds of this invention are inhibitors of HIV integrase and inhibitors of HTV replication.
- the inhibition of integrase in vitro and HTV replication in cells is a direct result of inhibiting the strand transfer reaction catalyzed by the recombinant integrase in vitro in HTV infected cells.
- the particular advantage of the present invention is highly specific inhibition of HTV integrase and HTV replication.
- the following references are of interest as background:
- WO 01/00578 discloses l-(aromatic- or heteroaromatic-substituted)-3-(heteroaromatic substituted)- 1, 3 -propanediones useful as HIV integrase inhibitors.
- US 2003/0055071 (corresponding to WO 02/30930), WO 02/30426, and WO 02/55079 each disclose certain 8-hydroxy-l,6-naphthyridine-7-carboxamides as HIV integrase inhibitors.
- WO 02/036734 discloses certain aza- and polyaza-naphthalenyl ketones to be HW integrase inhibitors.
- WO 03/016275 discloses certain compounds having integrase inhibitory activity.
- WO 03/35076 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides as HTV integrase inhibitors, and
- WO 03/35077 discloses certain N-substituted 5-hydroxy-6-oxo-l,6- dihydropyrimidine-4-carboxamides as HTV integrase inhibitors.
- WO 03/062204 discloses certain hydroxynaphthyridinone carboxamides that are useful as HIV integrase inhibitors.
- WO 04/004657 discloses certain hydroxypyrrole derivatives that are HIV integrase inhibitors.
- WO 2005/016927 discloses certain nitrogenous condensed ring compounds that are HIV integrase inhibitors.
- the present invention is directed to tricyclic analogs of hydroxy polyhydro-2,6- naphthyridine dione compounds. These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HTV, the treatment of infection by HIV and in the prevention, treatment, and delay in the onset of ADDS and/or ARC, either as compounds or their pharmaceutically acceptable salts or hydrates (when appropriate), 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, and pharmaceutically acceptable salts thereof:
- Rl is Ci-6 alkyl, R.J, or C ⁇ . ⁇ alkyl substituted with RJ, wherein RJ is CycA, AryA, HetA, or HetP;
- R2 is H or C 1-6 alkyl
- R3 is:
- Ci-6 alkyl (5) Ci_6 haloalkyl
- Y is a single bond, C ⁇ . ⁇ alkylene, O, 0-Ci_6 alkylene, Ci_6 alkylene-O, C(O), C(O)-Ci_6 alkylene, Ci-6 alkylene-C(O), C(O)-Ci_6 alkylene-O, C(O)-Ci_6 alkylene-O-Ci-6 alkylene, C(O)N(RA), C(O)N(RA)-C i_ ⁇ alkylene, Ci.6 alkylene-C(O)N(RA), Ci_6 alkylene-C(0)N(RA)-Ci_6 alkylene, S(O), S(0)2, S(O)-Ci-6 alkylene, S(O)2-Ci_6 alkylene, C ⁇ -(, alkylene-S(O), or Ci-6 alkylene-S(0)2; and RK is CycB, AryB, HetB, or HetQ;
- a benzene ring which is optionally substituted with a total of from 1 to 4 substituents wherein (a) from zero to 4 substituents are each independently one of substituents (1) to (25) as defined in part (i) of the definition of AryA and (b) from zero to 2 substituents are each independently one of the substituents (1) to (6) as defined in part (ii) of the definition of AryA, or
- each Z-RL 5 wherein: each Z is independently a single bond, C ⁇ . ⁇ alkylene, O, O-Ci-6 alkylene, C ⁇ . ⁇ alkylene-0, C(O), C(O)-Ci-6 alkylene, Ci -6 alkylene-C(O), C(0)-Ci_6 alkylene-O,
- each RL is independently CycC, AryC, HetC, or HetR;
- each RA is independently H or C 1-6 alkyl
- each RB is independently H or C ⁇ - ⁇ alkyl
- CycA is a C3_g cycloalkyl which is optionally substituted with a total of from 1 to 6 substituents, wherein:
- O-Ci-6 haloalkyl and (ii) from zero to 2 substituents are each independently:
- CycB independently has the same definition as CycA;
- each CycC independently has the same definition as CycA;
- 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:
- AryB independently has the same definition as AryA;
- each AryC independently has the same definition as AryA;
- 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:
- N(RA)CO2RB, and (ii) from zero to 2 substituents are each independently:
- HetB independently has the same definition as HetA;
- each HetC independently has the same definition as HetA;
- 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(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; 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 ⁇ -6 alkyl, C ⁇ . ⁇ haloalkyl, O-Ci-6 alkyl, O-Ci_6 haloalkyl, oxo, C(O)N(RA)RB ; C(O)C(O)N(RA)RB, C(O)RA
- substituents are each independently CycD, AryD, HetD, or C ⁇ . ⁇ alkyl substituted with CycD, AryD, HetD;
- HetQ independently has the same definition as HetP
- each HetR 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 ⁇ . ⁇ alkyl, OH, OCi _6 alkyl, or C ⁇ . ⁇ 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 (26) 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(0)2, wherein the saturated or mono-unsaturated heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, Ci.6 alkyl, Ci_6 haloalkyl, O-Ci-6 alkyl, O-Ci-6 haloalkyl, oxo, C(O)N(RA)RB 3 C(O)C(O)N(RA)RB 5 C(O)RA, CO2RA, SRA, S(O)RA, SO2RA, or S ⁇ 2N(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 fo ⁇ n of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein either one or both of the rings contain one or more of the heteroatoms, at least one ring is aromatic, each N is optionally in the form of an oxide, and each S in a ring which is not aromatic 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 ADDS, the delay in the onset of ADDS, the prophylaxis of ADDS, the prophylaxis of infection by HTV, and the treatment of infection by HTV.
- 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.
- the present invention includes compounds of Formula I above, and pharmaceutically acceptable salts thereof. These compounds and their pharmaceutically acceptable salts are HIV integrase inhibitors (e.g., HTV-I integrase inhibitors).
- a first embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 9-membered, saturated or mono-unsaturated heterocyclic ring containing in addition to the nitrogen shared with the naphthyridine ring from 1 to 3 heteroatoms independently selected from N, O, and S, wherein each S is optionally oxidized to S(O) or S(O)2; and wherein the saturated or mono- unsaturated heterocyclic ring is optionally substituted with a total of from 1 to 6 substituents, wherein:
- each Z is independently a single bond, C ⁇ . ⁇ alkylene, O, O-Ci_6 alkylene, C ⁇ - ⁇ alkylene-O, C(O), C(O) ⁇ Ci_6 alkylene, C ⁇ - ⁇ alkylene-C(O), C(O)-Ci_6 alkylene-O,
- a second embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is RJ or Ci_6 alkyl substituted with
- a third embodiment of the present invention is a compound of
- a fourth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is C 1.4 alkyl substituted with RJ; 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 Rl is (CH2)l-2R ⁇ or CH(CH3)-RJ; 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 Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is CH2-RJ; and all other variables are as originally defined or as defined in Embodiment El .
- a seventh 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 any one of the preceding embodiments.
- An eighth embodiment of the present invention is a compound of
- RJ is phenyl, naphthyl, 2,3- dihydrobenzo-l,4-dioxinyl, benzo-l,3-dioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, or quinazolinyl, any of which is optionally substituted with a total of from 1 to 4 substituents, wherein: (a) from zero to 4 substituents are each independently:
- Ci_6 haloalkyl (3) Ci_6 haloalkyl, (4) O-Ci-6 haloalkyl,
- substituents are each independently HetZ or C(O)-HetZ, wherein 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 Ci-4 alkyl, oxo, C(O)N(RA)RB 5 C(O)RA 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; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a ninth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is CH2-RJ; R ⁇ is as defined in
- Embodiment E8 and all other variables are as originally defined or as defined in Embodiment El.
- a tenth embodiment of the present invention (Embodiment ElO) is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is:
- 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 or 2 substituents each of which is independently C 1.4 alkyl, OH, OCi .4 alkyl, halogen, CN, C(O)N(RA)RB 5 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 C 1.4 alkyl, oxo, C(O)N(RA)RB, C(O)RA, 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;
- Vl and V2 are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy;
- V3 is:
- An eleventh embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Rl is CH2-RJ; and RJ is 4- fluorophenyl or 3-chloro-4-fluorophenyl; and all other variables are as originally defined or as defined in Embodiment El.
- a twelfth eleventh embodiment of the present invention is a compound of Fo ⁇ nula I, or a pharmaceutically acceptable salt thereof, wherein R2 is H or C ⁇ _g alkyl; and R3 is H, C ⁇ - ⁇ alkyl, C(O)N(RA)RB, S ⁇ 2N(RA)RB, or Ci_6 alkyl substituted with C(O)N(RA)RB or S02N(RA)RB, an d all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a thirteenth embodiment of the present invention is a compound of Fo ⁇ nula I 9 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are each independently H or C i_4 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a fourteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R2 and R.3 are both H; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a fifteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein ring A is:
- each R* is independently: (1) H, (2), Q-6 alkyl, (3) C(O)RA, (4) S ⁇ 2R A , (5) C ⁇ 2R A , or (6) Ci.6 alkyl substituted with OH, O-Ci-6 alkyl, N(RA)RB, C(O)N(RA)RB, C(O)RA C ⁇ 2R A , C(O)-N(RA)-C 1-6 alkylene-ORB with the proviso that the N(RA) moiety and the ORB moiety are not both attached to the same carbon of the Ci_6 alkylene moiety, S(O)RA, S ⁇ 2R A , S02N(RA)RB S
- Q is O or C(RA)RB ;
- ⁇ " 's denote the points at which ring A is attached to the remainder of the naphthyridine ring with which it is fused; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a sub-embodiment of Embodiment El 5 is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each R* is independently: (I) H, (2), Ci -6 alkyl, (3) C(O)RA, (4) S ⁇ 2R A , or (5) C ⁇ 2R A ; and ring A, Q and all other variables are as defined in Embodiment E15.
- a sixteenth embodiment of the present invention (Embodiment E 16) is a compound of
- Formula I or a pharmaceutically acceptable salt thereof, wherein each RA and RB is independently H or C 1-4 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a seventeenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each RA and RB is independently H or C 1-3 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- An eighteenth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each RA and RB is independently H or methyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a twentieth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein CycA, CycB, and CycC are each independently a C3.7 cycloalkyl which is optionally substituted with from 1 to 2 substituents each of which is independently Cl -4 alkyl, O-C1-.4 alkyl, phenyl, or benzyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- CycA, CycB, and CycC are each independently cyclopropane, cyclobutane, cyclopentane, or cyclohexane, any of which is optionally substituted withmethyLor phenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a twenty-first embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each aryl (i.e., the aryl incorporated into the definitions of AryA, AryB, and AryC) is independently selected from the group consisting of phenyl, naphthyl, tetrahydronaphthyl (tetralinyl), indenyl, anthracenyl, or fiuorenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- each aryl is independently selected from the group consisting of phenyl and naphthyl.
- each aryl is phenyl.
- a twenty-second embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each heteroaryl (i.e., the heteroaryl incorporated into the definitions of HetA, HetB, and HetC) is independently selected from the group consisting of pyrrolyl, pyrazolyl, thienyl, furanyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl (or pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopi
- quinazolinyl 2,3-dihydrobenzo-l,4-dioxinyl (i.e., Oft O ), and benzo-l,3-dioxolyl (i.e., ); and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- each heteroaryl is independently a 5- or 6-membered heteroaromatic ring selected from the group consisitng of pyrrolyl, pyrazolyl, thienyl, furanyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl (or pyridyl), pyrazinyl, pyrimidinyl, and pyridazinyl.
- a twenty-third embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein HetP and HetQ are each independently a 4- to 7-membered, saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or SO2; wherein the heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C 1.4 alkyl, Ci .4 haloalkyl, O-C1.4 alkyl, OCi .4 haloalkyl, oxo, C(O)N(RA)RB 5 C(O)C(O)N(RA)RB 5 C(O)RA CO2RA, SRA 5 S(O)RA 5 SO2RA, or S ⁇ 2N(RA)RB ; an d all other variables are as originally defined or as defined in any one of the preceding embodiments, hi an
- a twenty-fourth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each CycD is independently a C3-.7 cycloalkyl which is optionally substituted with from 1 to 2 substituents each of which is independently Cj_4 alkyl, O-C1.4 alkyl, phenyl, or benzyl.
- each CycD is independently cyclopropane, cyclobutane, cyclopentane, or cyclohexane, any of which is optionally substituted with methyl or phenyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a twenty-fifth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each AryD is independently phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently (1) C 1.4 alkyl, (2) OH 5 (3) O-C1.4 alkyl, (4) C1.4 haloalkyl, (5) O-C1.4 haloalkyl, (6) halogen, (7) CN, (8) N(RA)RB, (9) C(O)N(RA)RB, (10) C(O)RA (i i) C(O)ORA (12) SRA (13) S(O)RA (14) SO2RA, (15) N(RA)SO2R B , (16) N(RA)SO2N(RA)RB, (17) N(RA)C(O)RB, or (18) N(RA)C(0)C(0)N(RA)RB ; and all other variables are as originally defined or as defined in any one of the preceding embodiments
- a twenty-sixth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each AryD is independently phenyl which is optionally substituted with from 1 to 3 substituents each of which is independently (1) Cj_4 alkyl, (2) C1-4 haloalkyl, (3) OH, (4) O-C1.4 alkyl, (5) halogen, (6) CN, (7) C(0)NH2, (8) C(O)NH(C 1 -4 alkyl), (9) C(O)N(C 1.4 alkyl)2, or ( 10) SO2-C ⁇ .4 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- the 1 to 3 substituents are each independently selected from the group consisting of CH3, CF3, OH, OCH3, Cl, Br, F, CN, C(0)NH2, C(0)NH(CH3), C(O)N(CH3)2, or SO2CH3.
- a twenty-seventh embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each HetD is independently a 5- or 6-membered heteroaromatic ring independently selected from the group consisting of pyrrolyl, pyrazolyl, thienyl, furanyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl (or pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl; wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently (1) C1.4 alkyl, (2) OH, (3) O-C1.4 alkyl, (4) Ci
- a twenty-eighth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each HetD is independently a 5- or 6-membered heteroaromatic ring independently selected from the group consisting of the heteroaromatic rings set forth in Embodiment E27, wherein the heteroaromatic ring is optionally substituted with from 1 to 3 substituents each of which is independently (1) C 1.4 alkyl, (2) C 1.4 haloalkyl, (3) OH, (4) O-Ci-4 alkyl, (5) halogen, (6) CN, (7) C(0)NH2, (8) C(0)NH(Ci_4 alkyl), (9) C(0)N(Ci_4 alkyl)2, or (10) SO2-C1-4 alkyl; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- the 1 to 3 substituents are each independently selected from the group consisting of CH3, CF3, OH, OCH3, Cl, Br, F, CN, C(0)NH2, C(O)NH(CH3), C(O)N(CH3)2, or SO2CH3.
- a twenty-ninth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each HetD is independently 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 or 2 substituents each of which is independently C 1.4 alkyl, OH, O-Ci-4 alkyl, halogen, CN, C(O)N(RA)RB, C(O)RA C(O)ORA, or SO2RA; and all other variables are as originally defined or as defined in any one of the preceding embodiments.
- a thirtieth embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each HetZ is independently a 4- to 7- membered, saturated heterocyclic ring containing from 1 to 3 heteroatoms independently selected from N, O and S, where each S is optionally oxidized to S(O) or SO2; wherein the heterocyclic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, Ci .4 alkyl, Ci_4 haloalkyl, O-C1.4 alkyl, O-C1.4 haloalkyl, oxo, C(O)N(RA)RB 5 C(O)C(O)N(RA)RB 5 C(O)RA CO2RA, SRA 5 S(O)RA 5 SO2RA, or SO2N(RA)RB ; an d all other variables are as originally defined or as defined in any one of the preceding embodiments.
- each HetZ is independently a saturated heterocyclic ring selected from the group consisting of azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl, wherein the ring is optionally substituted with from 1 to 2 substituents each of which is independently Ci_4 alkyl or oxo.
- a thirty-second embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein each Z is independently a single bond, (CH 2 )l-2, O, 0-(CH 2 ) 1-2, (CH 2 ) 1-2-0, C(O), C(O)-(CH 2 ) 1-2, (CH 2 ) 1-2-C(O), C(O)-(CH 2 )l-2-O, C(OMCH 2 )l-2-O-(CH 2 )l-2, C(O)N(RA) 5 C(O)N(RA)-(CH 2 ) 1-2, (CH 2 )L 2 -C(O)N(RA), (CH 2 )i- 2 -C(O)N(RA)-(CH 2 )i_2, S(O), S(O) 2 , S(O)-(CH 2 ) 1-2, S(O) 2 -(CH 2 ) 1-2, (CH 2 ) 1-2-
- Rl, R2 and R3 are each as originally defined above or as defined in any one of the preceding embodiments;
- n is an integer equal to zero, 1, 2, or 3;
- W is O orN-R8;
- R4 is: (1) H,
- each R5 is independently:
- each R9 is independently H or Ci -6 alkyl
- R6 and R7 are each independently H, C ⁇ .(, alkyl, or Ci_6 alkyl substituted with OH;
- R8 is: 5 (1) H
- n O means a 5-membered ring with a direct bond between the ring
- a subclass of the first class (alternatively referred to as “Subclass SCl-I ”) includes compounds of Formula Ha and lib, and pharmaceutically acceptable salts thereof, wherein Rl is as defined in Embodiment ElO; and all other variables are as originally defined Class Cl.
- a second class of the present invention (Class C2) includes compounds of Formula Ha' and lib' and pharmaceutically acceptable salts thereof: R 3 °v w ⁇ R4
- R4 is H or Ci_6 alkyl
- each R5 is independently H or Ci_6 alkyl
- R6 and R7 are each independently H or Ci -6 alkyl
- RB is:
- a subclass of the second class includes compounds of Formula Ha' and lib', and pharmaceutically acceptable salts thereof, wherein W is O, NH, or N-C i_6 alkyl; and all other variables are as originally defined in the second class.
- Subclass SC2-2 Another subclass of the second class (Subclass SC2-2) includes compounds of Formula Ha' and Hb', and pharmaceutically acceptable salts thereof, wherein W is O, NH, or N-C 1.4 alkyl; and all other variables are as originally defined in the second class.
- Another subclass of the second class includes compounds of Formula Ha 1 and Hb', and pharmaceutically acceptable salts thereof, wherein W is O; and all other variables are as originally defined in the second class.
- Still another subclass of the second class includes compounds of Formula Ha' and Hb', and pharmaceutically acceptable salts thereof, wherein W is NH or N-C 1.4 alkyl; and all other variables are as originally defined in the second class.
- Still another subclass of the second class includes compounds of Formula Ha' and lib', and pharmaceutically acceptable salts thereof, wherein W is NH or N-C 1.3 alkyl; and all other variables are as originally defined in the second class.
- Still another subclass of the second class includes compounds of Formula Ha' and lib', and pharmaceutically acceptable salts thereof, wherein W is NH or N-CH3 ; and all other variables are as originally defined in the second class.
- Still another subclass of the second class includes compounds of Formula Ila' and lib', and pharmaceutically acceptable salts thereof, wherein Z is a single bond, (CH 2 )l-2, O, O-(CH 2 )i-2, (CH 2 )l-2-O, C(O), C(O)-(CH 2 ) 1-2, (CH 2 ) l- 2 -C(O), C(O)-(CH 2 ) l- 2 -O, C(O)-(CH 2 )i-2-O-(CH 2 )i_ 2 , C(O)N(RA), C(O)N(RA)-(CH 2 ) i_ 2 , (CH 2 ) I_ 2 -C(O)N(RA), (CH 2 )I- 2 -C(O)N(RA)-(CH 2 )I- 2 , S(O), S(O) 2 , S(O>(CH2)l-2, S(O) 2 -(CH 2 -(CH 2
- a third class of the present invention includes compounds of Formula IHa, IHb, Die, and Hid and pharmaceutically acceptable salts thereof:
- R2 and R.3 are each independently H or C 1.4 alkyl
- R4 is:
- R5a is H, C1.4 alkyl, OH or -HetR;
- R9a is H or C1.4 alkyl
- R5a and R9a together form oxo
- R5b is H, Ci-4 alkyL or OH
- R9b is H or Ci_4 alkyl
- R5c is H, Ci_4 alkyl, or Ci-4 alkyl substituted with OH;
- R9c is H or C 1.4 alkyl
- R ⁇ 5 and R7 is H, Ci -4 alkyl, or C 1.4 alkyl substituted with OH, and the other of R ⁇ and R? is H or Ci-4 alkyl;
- R8 is:
- HetC 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 or 2 substituents each of which is independently Ci-4 alkyl, OH, O-C1.4 alkyl, halogen, CN, C(O)N(RA)RB 5 C(O)RA C(O)ORA, O r SO 2 RA;
- HetR 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 Ci-4 alkyl, oxo, C(O)N(RA)RB, C(O)RA, CO 2 RA, O r SO 2 RA;
- each RA is independently H or C 1.4 alkyl
- each RB is independently H or C 1.4 alkyl
- Vl 5 V2 and V3 are as defined in Embodiment ElO.
- R5a, R5b an d R5C m class C3, when R5a is OH or
- R ⁇ b and R5c are each independently H or C 1.4 alkyl.
- a fourth class of the present invention includes compounds of Formula Ufa' and Did' and pharmaceutically acceptable salts thereof:
- n is an integer equal to zero, 1, 2 or 3;
- 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 or 2 substituents each of which is independently Cj .4 alkyl, OH, O-Cj-4 alkyl, halogen, CN, C(O)N(RA)RB 5 C(O)RA, C(O)ORA, O r S ⁇ 2R A ,
- 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 C 1.4 alkyl, oxo, C(0)N(RA)RB ; C(O)RA, CO2RA, or SO2R.A 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;
- Vl and V ⁇ are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy;
- V3 is:
- W is O, NH, N-C1.4 alkyl, NC(O)-CM alkyl, N-C(O)O-CM alkyl, or N-SO2-Q-4 alkyl;
- R2 and R3 are each independently H or C 1.4 alkyl
- R6 and R? are each independently H or C 1.4 alkyl; each RA is independently H or C 1.4 alkyl; and
- each R.B is independently H or Cj-4 alkyl.
- a subclass of the fourth class includes compounds of Formula DIa' and
- n is an integer equal to 1, 2 or 3;
- Vl and V2 are each independently:
- Vl and V2 are respectively located on adjacent carbons in the phenyl ring and together form methylenedioxy or ethylenedioxy;
- V 3 is H, halogen, Ci .4 alkyl, or O-Ci-4 alkyl;
- n is an integer equal to 1, 2 or 3;
- Vl and V2 are each independently:
- V3 is H, Cl, Br, F, CH 3 , or OCH 3;
- W is O, NH, or N-CH 3 ;
- R2 and R3 are both H;
- R6 and R7 are each independently H or CH 3 .
- a sixth class of the present invention (Class C6) includes compounds of Formula Eta, mb, Hie and Did and pharmaceutically acceptable salts thereof, wherein:
- R2 and R3 are each independently H or CH 3 ;
- R4 is:
- R5a is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OH or -HetR;
- R9a is H 5 CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 ;
- R5a and R ⁇ a together form oxo
- R5b is H 5 CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , or OH;
- R9b is H 5 CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 ;
- R5c is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , or (CH 2 )i_ 3 -OH;
- R9c is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 ;
- R5a R5b an d R5c when one of R5a R5b an d R5c is other than H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 , then the other two of R5a R5b an d RSc is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , or CH(CH 3 ) 2 ;
- R6 and R7 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 or (CH 2 )IJ 3 -OH, and the other of R ⁇ and R7 is H or CH 3 ;
- V is C(O)N(RA)RB 3 C(O)RA C ⁇ 2R A , S(O)RA 5 SO2RA, or
- HetC is a 5-membered heteroaromatic ring selected from the group consisting of:
- HetR is a 5- or 6-membered saturated heterocyclic ring selected from the group consisting of:
- each RA is independently H or CH3;
- each RB is independently H or CH3;
- Vl and V2 are each independently:
- V3 is H, Cl, Br, F, CH3, or OCH 3 .
- 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 64.
- 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 9.
- 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 10 to 64.
- Another embodiment of the present invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, as originally defined or as defined in any of the foregoing embodiments, classes, subclasses, aspects, or features, wherein the compound or its salt is substantially pure.
- substantially pure means that the compound or its salt is present (e.g., in a product isolated from a chemical reaction or a metabolic process) in an amount of at least about 90 wt.% (e.g., from about 95 wt.% to 100 wt.%), preferably at least about 95 wt.% (e.g., from about 98 wt.% to 100 wt.%), more preferably at least about 99 wt.%, and most preferably 100 wt.%.
- the level of purity of the compounds and salts can be determined using standard methods of analysis. A compound or salt of 100% purity can alternatively be described as one which is free of detectable impurities as determined by one or more standard methods of analysis.
- 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:
- composition comprising an effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
- a pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I and a pharmaceutically acceptable carrier.
- an anti-FflV agent selected from the group consisting of HTV antiviral agents, immunomodulators, and anti-infective agents.
- composition of (c), wherein the anti-HTV agent is an antiviral selected from the group consisting of HIV protease inhibitors, non-nucleoside HTV reverse transcriptase inhibitors, and nucleoside HTV reverse transcriptase inhibitors.
- a pharmaceutical combination which is (i) a compound of Formula I and (ii) an anti-FflV agent selected from the group consisting of HIV antiviral agents, immunomodulators, and anti- infective agents; wherein the compound of Formula I and the anti-HTV agent are each employed in an amount that renders the combination effective for the inhibition of HTV integrase, for the treatment or prophylaxis of infection by FHV, or for the treatment, prophylaxis or delay in the onset of AIDS.
- anti-HTV agent is an antiviral selected from the group consisting of HTV protease inhibitors, non-nucleoside HTV reverse transcriptase inhibitors and nucleoside FHV reverse transcriptase inhibitors.
- a method of inhibiting HIV integrase in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I.
- (h) A method for the treatment or prophylaxis of infection by HTV in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I.
- Q) A method for the treatment, prophylaxis, or delay in the onset of AIDS in a subject in need thereof which comprises administering to the subject an effective amount of a compound of Formula I.
- a method of inhibiting HTV 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 HTV 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).
- a method for the treatment, prophylaxis, or delay in the onset of AIDS in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b), (c) or (d) or the combination of (e) or (f).
- the present invention also includes a compound of the present invention (i) for use in, (ii) for use as a medicament for, or (iii) for use in the preparation of a medicament for: (a) the inhibition of HTV integrase, (b) treatment or prophylaxis of infection by HW, or (c) treatment, prophylaxis, or delay in the onset of AIDS.
- the compounds of the present invention can optionally be employed in combination with one or more anti-HTV agents selected from HTV antiviral agents, anti-infective agents, and immunomodulators.
- Additional embodiments of the invention include the pharmaceutical compositions, combinations and methods set forth in (a)-(n) above and the uses set forth in the preceding paragraph, wherein the compound of the present invention employed therein is a compound of one of the embodiments, aspects, classes, subclasses, or features of the compounds described above. In all of these embodiments, the compound may optionally be used in the form of a pharmaceutically acceptable salt.
- the present invention also includes prodrugs of the compounds of Formula I.
- prodrug refers to a derivative of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which is converted in vivo into Compound I.
- Prodrugs of compounds of Formula I can exhibit enhanced solubility, absorption, and/or lipophilicity compared to the compounds per se, thereby resulting in increased bioavailability and efficacy.
- the in vivo conversion of the prodrug can be the result of an enzyme-catalyzed chemical reaction, a metabolic chemical reaction, and/or a spontaneous chemical reaction (e.g., solvolysis).
- the prodrug can be an ester or an amide
- the prodrug can be an amide, carbamate, imine, or a Mannich base.
- One or more functional groups in Compound I can be derivatized to provide a prodrug thereof.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, edited by H. Bundgaard, Elsevier, 1985; C. S. Larsen and J. Ostergaard, "Design and application of prodrugs" in: Textbook of Drug Design and Discovery. 3 rd edition, edited by C. S.
- Prodrugs of compounds of Formula I can also be selected and prepared by application of the descriptions in WO 2005/070901 and WO 2005/117904, both herein incorporated by reference in their entireties.
- alkyl refers to any linear or branched chain alkyl group having a number of carbon atoms in the specified range.
- C 1-6 alkyl (or “Cl-C6 alkyl”) refers to all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso ⁇ , sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- Ci_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 (or alternatively an "alkanediyl”) having a number of carbon atoms in the specified range.
- -Ci_6 alkylene- refers to any of the Cl to C ⁇ linear or branched alkylenes.
- a class of alkylenes of particular interest with respect to the invention is -(CH2)l-6-, and subclasses of particular interest include -(CH2)l-4-, -(CH2)l-3-, -(CH2)l-2- > and -Cflt ⁇ -.
- alkylene -CH(CH3)- is also of interest.
- 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.S cycloalkyl (or “C3-C8 cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
- haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms has been replaced with a halogen (i.e., F, Cl, Br and/or I).
- a halogen i.e., F, Cl, Br and/or I.
- Ci_6 haloalkyl or “Ci-C ⁇ haloalkyl” refers to a Cl to C ⁇ 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 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, and so forth.
- an aryl or heteroaryl described as optionally substituted with "from 1 to 5 substituents" is intended to include as aspects thereof, an aryl or heteroaryl optionally substituted with 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents, 2 to 5 substituents, 2 to 4 substituents, 2 to 3 substituents, 3 to 5 substituents, 3 to 4 substituents, 1 substituent, 2 substituents, 3 substituents, 4 substituents, and 5 substituents.
- any variable e.g., RA 5 RB 5 O r AryD
- its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- Y C ⁇ S alkylene-C(O) (e.g., (CH2) 1 -2-C(O) )
- RK is attached to the carbonyl; i.e., C i _6 alkylene-C(O)-RK (e.g.,
- 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. 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 heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.
- a ring e.g., aryl, a heteroaromatic ring, or a saturated heterocyclic ring
- 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).
- 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.
- Compounds of the present invention having a hydroxy substituent 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.
- the compounds of the present inventions are useful in the inhibition of HTV integrase (e.g., HIV-I integrase), the prophylaxis or treatment of infection by HTV and the prophylaxis, treatment or the delay in the onset of consequent pathological conditions such as AIDS.
- HTV integrase e.g., HIV-I integrase
- the prophylaxis of AIDS, treating AIDS, delaying the onset of AIDS, the prophylaxis of infection by HTV, or treating infection by HTV is defined as including, but not limited to, treatment of a wide range of states of HIV infection: ADDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HTV.
- the compounds of this invention are useful in treating infection by HTV after suspected past exposure to HTV 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 en:zyme 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 HTV 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, trifluoroacetic acid, or benzoic acid.
- 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.
- alkali metal salts e.g., sodium or potassium salts
- alkaline earth metal salts e.g., calcium or magnesium 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 a prodrug of the compound to the individual in need of treatment or prophylaxis.
- a compound of the invention or a prodrug thereof is provided in combination with one or more other active agents (e.g., antiviral agents useful for the prophylaxis or treatment of EDV infection or AIDS)
- “administration” and its variants are each understood to include provision of the compound or prodrug 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.
- 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.
- pharmaceutically acceptable is meant that the ingredients of the pharmaceutical composition must be compatible with each other and not deleterious to the recipient thereof.
- 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").
- 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 rectally, 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.
- 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.
- Another preferred dosage range is about 0.1 to about 100 mg/kg body weight per day orally in single or 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-HTV agent is any agent which is directly or indirectly effective in the inhibition of HTV integrase or another enzyme required for HTV replication or infection, the treatment or prophylaxis of HTV infection, and/or the treatment, prophylaxis or delay in the onset of AIDS. It is understood that an anti-HTV agent is effective in treating, preventing, or delaying the onset of HTV 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 HTV antivirals, imunomodulators, antiinfectives, or vaccines useful for treating HTV infection or AIDS, such as those disclosed in Table 1 of WO 01/38332 or in the Table in WO 02/30930.
- HtV antivirals for use in combination with the compounds of the present invention include, for example, HTV protease inhibitors (e.g., indinavir, atazanavir, lopinavir optionally with ritonavir, saquinavir, or nelfinavir), nucleoside HTV reverse transcriptase inhibitors (e.g., abacavir, lamivudine (3TC), zidovudine (AZT), or tenofovir), and non-nucleoside HTV reverse transcriptase inhibitors (e.g., efavirenz or nevirapine).
- HTV protease inhibitors e.g., indinavir, atazanavir, lopinavir optionally with ritonavir, saquinavir, or nelfinavir
- nucleoside HTV reverse transcriptase inhibitors e.g., abacavir, lamivudin
- HTV antivirals 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, 58 th edition, Thomson PDR, 2004, or the 59 th edition thereof, 2005.
- the dosage ranges for a compound of the invention in these combinations are the same as those set forth above. It is understood that pharmaceutically acceptable salts of the compounds of the invention and/or the other agents (e.g., indinavir sulfate) can be used as well.
- 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 5,6,7,8-tetrahydro-2,6-naphthyridine-l- carboxylate intermediates useful for making compounds of the present invention.
- lactam 1-1 can be alkylated with an appropriate alkyl halide in the presence of a deprotonating agent (e.g., NaH, NaHMDS, or LHMDS) to give 1-2, using methods as described in Jerry March,
- Piperidin-2-one 1-2 can be converted to the corresponding dihydropyridinone compound 1-5 following the two step procedure set forth in Meyers et al., Tet. Lett.
- lactam can be treated with base (e.g., LHMDS, LDA or Na HMDS) and methyl benzene sulfinate to give intermediate 1-4, which can then be treated by heating in a high boiling solvent (e.g., toluene or xylenes) and optionally in the presence of base (e.g., Na2CO3 or K2CO3) to effect the elimination to 1-5.
- base e.g., LHMDS, LDA or Na HMDS
- base e.g., Na2CO3 or K2CO3
- oxazoles of the type 1-9 can readily be prepared by acylating amino acid ester 1-6 with an oxalate ester 1-7 in the presence of base (e.g., tertiary amines such as TEA, DIPEA, or pyridine) to afford acylated compound 1-8, which can then be cyclized and dehydrated (using a dehydrating agent such as P2O5) in the manner described in Krapcho et al. J. Heterocyclic Client. 1995, 32, 1693-1702 to afford oxazole 1-9.
- base e.g., tertiary amines such as TEA, DIPEA, or pyridine
- P2O5 dehydrating agent
- Diels- Alder reaction of 1-9 and 1-5 optionally in the presence of water or an acid (e.g., AcOH or TFA) (preferably in the presence of water as described in "Catalysis of Diels-Alder Reactions in Water and in Hydrogen-Bonding Environments", Wittkopp, A. & Schreiner, P. R. in: Chemistry of Dienes and Polyenes. 2000, Vol. 2, John Wiley & Sons, pp. 1029-1088), will then provide the desired napthyridine intermediate 1-10.
- R x H, C 1-6 alkyl, or
- Scheme 2 depicts a method for preparing naphthyridine carboxylates and carboxamides embraced by the present invention from naphthyridine intermediate 1-10, wherein the intermediate 1-10 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 N-oxide 2-1, which can then be treated as described in Suzuki et al., J. Med. Chem.
- a suitable oxidizing agent e.g., hydrogen peroxide or m-chloroperbenzoic acid
- the intermediate 1-10 can be treated with trimethylsilyldiazomethane to provide the O-methyl ether selectively.
- a suitable base e.g., magnesium alkoxide
- a suitable dihaloalkane e.g., l-bromo-4-chlorobutane or l-bromo-3- chloropropane
- halide 3-1 Treatment of halide 3-1 with a primary amine in the presence or absence of an iodide catalyst such as potassium iodide or tetra-n-butylammonium iodide provided the aminoester intermediate 3-2.
- an iodide catalyst such as potassium iodide or tetra-n-butylammonium iodide
- Base catalyzed hydrolysis of the amino-ester 3-2 provided the corresponding aminoacid which was treated with an amide coupling reagent such as EDC or BOP to provide the tricyclic napthyridine products 3-3.
- the RY substituent on 3-3 can be removed under appropriate conditions to provide products 3-4.
- Scheme 4 depicts a method for preparing pyrazino[2,l-a]-2,6-naphthyridines 4-1 and 4-2 embraced by the present invention from naphthyridine intermediate 2-2, wherein the intermediate 2-2 is treated with a suitable base (e.g., magnesium alkoxide, cesium carbonate, or potassium carbonate) and an appropriately protected ⁇ -amino- ⁇ -haloalkane (e.g., a protected l-amino-2-haloethane such as tert-butyl (2-bromoethyl)carbamate) to provide the tricyclic napthyridine products 4-1.
- a suitable base and alkylating reagent e.g., an alkyl halide
- Scheme 5 depicts a method for preparing oxazino[2,l-a]-2,6-naphthyridines 5-1 embraced by the present invention from naphthyridine intermediate 2-2, wherein the intermediate 2-2 is treated with a suitable base (e.g., magnesium alkoxide, cesium carbonate, or potassium carbonate) and a suitable ⁇ , ⁇ -dihaloalkane (e.g., a dihaloethane such as l-bromo-2-chloroethane) to provide the tricyclic napthyridine products 5-1.
- a suitable base e.g., magnesium alkoxide, cesium carbonate, or potassium carbonate
- a suitable ⁇ , ⁇ -dihaloalkane e.g., a dihaloethane such as l-bromo-2-chloroethane
- Oxazepino and oxazocino analogs can be similarly prepared using a suitable dihaloalkane such
- Scheme 6 depicts a method for preparing imidazo[2,l-a]-2,6-naphthyridines 6-4 and 6-5 embraced by the present invention from naphthyridine intermediate 2-2, wherein the intermediate 2-2 is treated with a suitable base (e.g., magnesium alkoxide, cesium carbonate, or potassium carbonate) and a suitable substituted alkyl haloacetate (e.g., tert-butyl bromoacetate) to provide the alkylation product 6- 1.
- a suitable base e.g., magnesium alkoxide, cesium carbonate, or potassium carbonate
- a suitable substituted alkyl haloacetate e.g., tert-butyl bromoacetate
- alkyl H alkyl
- Scheme 7 depicts a method for preparing 3,4,5,6,12,13-hexahydro-2H[l,4]diazocmo[2,l- a]-2,6-naphthyridine-l,8,10(llH) ⁇ trione 7-3 from naphthyridine intermediate 2-5, wherein the intermediate 2-5 is treated with a suitable substituted aminoalcohol and an amide coupling reagent (e.g., EDC or BOP) to provide the amide product 7-1.
- a suitable substituted aminoalcohol e.g., EDC or BOP
- Scheme 8 depicts a method for preparing oxazino[2,l-a]-2,6-naphthyridines from naphthyridine intermediate 2-2, wherein the intermediate 2-2 is treated with a suitable base (e.g., magnesium alkoxide, cesium carbonate, or potassium carbonate) and a suitable allyl halide (e.g., allyl bromide) to provide the allylated napthyridine product 8-1.
- a suitable base e.g., magnesium alkoxide, cesium carbonate, or potassium carbonate
- a suitable allyl halide e.g., allyl bromide
- 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.
- Step 2 l-(3-Chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(lH)-one
- a cold (-20 0 C) solution of 1 -(3-chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) in anhydrous tetrahydrofuran (5 L) under an atmosphere of nitrogen a solution of lithium bis(trimethylsilyl)amide (3.09 L, 3.09 mol; IM in THF) was added over a period of 40 minutes with the temperature of the reaction maintained at -20 0 C. After the addition was complete, the reaction mixture was stirred at -20 0 C for one hour.
- Methyl benzene sulfonate (231 mL, 1.69 mol) was added to the reaction mixture over a period of 30 minutes. The reaction mixture was stirred at -20 0 C for 30 minutes. The product mixture was diluted with ethyl acetate (4 L) and washed with water (four times; 2 L each time). The organic extract was concentrated under vacuum. The residue was dissolved in toluene (4 L), treated with solid sodium carbonate (500 g), and heated at 100 0 C for one hour. The product mixture was diluted with ethyl acetate (4 L) and washed with water (4 times; 2 L each). The organic extract was concentrated under vacuum.
- Step 5 Ethyl 5-butoxy-l,3-oxazole-2-carboxylate To a solution of butyl N-[ethoxy(oxo)acetyl]glycinate (783 g, 3.38 mol) in acetonitrile (8
- Step 7 Ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine- 1 -carboxylate 2-oxide
- Step 8 Ethyl 3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine- 1 -carboxylate
- Step 9 Methyl 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine- 1 -carboxylate
- Step 10 Methyl 2-(4-chlorobutyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1 -carboxylate
- Step 12 6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1 -carboxylic acid
- Step 13 l l-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-3,4,5,6,12,13-hexahydro-
- Step 2 ll-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro- 5 2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8,10(l lH)-trione
- the titled compound was prepared in a manner similar to that described in Example 1, steps 12 and 13, substituting methyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]- 3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-l-carboxylate with methyl 6-(3-chloro-4- fluorobenzyl)-4-methoxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine- 0 1-carboxylate.
- Step 3 1 l-(4-Fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6, 12, 13-hexahydro-
- Step 1 10-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2-(4-methoxybenzyl)-2,3,4,5,l l,12- hexahydro[ 1 ,4]diazepino[2, 1 -a]-2,6-naphthyridine- 1 ,7,9( 10H)-trione
- the titled compound was prepared in a manner similar to that described in Example 1, substituting l-bromo-4-chlorobutane with l-bromo-3-chloropropane in Step 10, and replacing methylamine with 4-methoxybenzylamine in Step 11.
- ES MS M+l 526
- Step 2 10-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,5,l l,12-hexahydro[l,4]diazepino[2,l-a]-
- the resultant DMSO solution was treated with l-bromo-2-chloroethane (0.28 g, 1.97 mmol) and stirred at 60 0 C under an atmosphere of nitrogen overnight.
- the reaction mixture was diluted with ethyl acetate and dilute hydrochloric acid.
- the organic extract was washed with aqueous sodium sulfite, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography.
- Step 1 Methyl 2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-
- Step 2 Methyl 2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluoroben2yl)-4-methoxy-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-l-carboxylate
- Step 3 2-(2-tert-Butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-metlioxy-3,5-dioxo- 2,3,5,6,7,8-hexahydro-2,6-naphthyridine-l-carboxylic acid
- Step 5 8-(3-Chloro-4-fluoroben2yl)-6-methoxy-l,8,9,10-tetrahydroimidazo[2,l-a]-2,6- naphthyridine-2,5,6(3H)-trione
- Step 6 8-(3-Chloro-4-fluorobenzyl)-6-methoxy-l,3-dimethyl-l,8,9,10-tetrahydroimidazo[2,l-a]-
- Step 7 8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-l,3-dimethyl-l,8,9,10-tetral ⁇ ydroimidazo[2,l-a]-
- Step 2 Ethyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6- naphthyridine- 1 -carboxylate
- ethyl 6-(3 ⁇ chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7 s 8- tetrahydro-2,6-naphthyridine-l -carboxylate 208 g, 0.55 mol
- a solution of (trimethyl-silyl)diazomethane (600 mL, 1.2 mol; 2M) in hexanes was added over a period of 1 hour with the reaction temperature maintained below 15 0 C.
- Step 3 Ethyl 3-(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-4-metlioxy-5-oxo-5 5 6,7,8-tetrahydro-2,6- naphthyridine- 1 -carboxylate
- a cold (5 °C) mixture of ethyl 6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8- tetrahydro-2,6-naphthyridine-l-carboxylate 199 g, 0.51 mol
- urea hydrogen peroxide 100 g, 1.06 mol
- dichloromethane 1.5 L
- the resultant homogeneous solution was stirred at 20 0 C for 30 minutes and cooled back to 5 0 C.
- the reaction mixture was treated with aqueous potassium hydrogen phosphate (pH of aqueous extract increased to ⁇ 8), followed by slow addition of freshly prepared aqueous sodium bisulfite solution with the temperature of the product mixture maintained below 25 °C.
- the organic extract was separated and the aqueous fraction extracted with toluene (2X). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum.
- Step 4 6-(3-Chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6- naphthyridine-1-carboxylic acid
- Step 5 N-[2-(Benzyloxy)ethyl]-4- ⁇ [te7-/-butyl(dimethyl)silyl]oxy ⁇ butan-1 -amine
- Step 6 N-[2-(Benzyloxy)ethyl]-N-(4- ⁇ [rert-butyl(dimethyl)silyl]oxy ⁇ butyl)-6-(3-chloro-4- fluorobenzyl)-4-methoxy-3 ,5-dioxo-2,3 ,5,6,7,8-hexahydro-2,6-naphthyridine- 1 - carboxamide
- Step 7 N-[2-(Benzyloxy)ethyl]-N-(4-hydroxybutyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3 ,5- dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-l-carboxamide
- Step 8 N-[2-(Benzyloxy)ethyl]-N-(4-methanesulfonyloxybutyl)-6-(3-chloro-4-fluorobenzyl)-4- methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-l-carboxamide
- N-[2-(benzyloxy)ethyl]-N-(4-hydroxybutyl)-6-(3-chloro-4- fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-l-carboxamide (0.20 g, 0.34 mmol) and
- Step 9 l l-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyloxy)ethyl]-3,4,5,6,12,13- hexahydro-2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8,10(l lH)-trione
- Step 10 ll-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-[2-(acetyloxy)ethyl]-3,4,5,6,12,13- hexahydro-2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8,10(l lH)-trione
- Step 1 fer/-Buryl [(4-hydroxybutyl)amino] acetate
- Step 2 tert-Butyl [1 l-(3-chloro-4-fluorobenzyl)-9-methoxy-l,8,10-trioxo-
- Step 3 [1 l-(3-ChloiO-4-fluorobenzyl)-9-hydroxy-l,8,10-trioxo-l,3,4,5,6,8,10,l 1,12,13-deca- hydro-2H-[l,4]diazocino[2,l-a]-2,6-naphthyridin-2-yl]acetic acid
- a mixture of tert-butyl [1 l-(3-chloro-4-fluorobenzyl)-9-methoxy-l,8,10-trioxo- 1,3,4,5,6,840414243-decahydro-2H-[l,4]diazocino[2,l-a]-2,6-naphthyridin-2-yl]acetate (50 mg, 0.09 mmol) and 33% hydrogen bromide in acetic acid (1 mL) in dioxane (1 mL) was stirred at room temperature for 1 hour.
- Step l 2-[l l-(3-Chloro-4-fluorobenzyl)-9-hydroxy-l,8,10-trioxo-l,3,4,5,6,8,10,l 1,12,13-deca- hydro-2H-[l,4]diazocino[2,l-a]-2,6-naphthyridin-2-yl]-N,N-dimethylacetamide Asolution of [1 l-(3-chloro-4-fluorobenzyl)-9-hydroxy-l,8,10-trioxo-
- Step 1 ll-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-(2-hydroxyethyl)-3,4,5,6,12,13-hexahydro-
- Step 2 l l-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-[2-(methansulfonyloxy)ethyl]-3,4,5,6,12,13- hexahydro-2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8,10(l lH)-trione
- 1 l-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-hydroxyethyl)- 3,4,5,6,12,13-hexahydro-2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8,10(l lH)-trione 250 mg, 0.52 mmol
- diisopropylethylamine (0.19 mL, 1.05 mmol
- reaction mixture was allowed to warm up to room temperature and was stirred at room temperature for 2 hour.
- product mixture was diluted with dichloromethane and washed with aq ammonium chloride.
- organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to afford the title compound. This material was used in the following reaction without further purification.
- Step 3 ll-(3-Chloro-4-fluoroben2yl)-9-methoxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13- hexahydro-2H[ 1 ,4]diazocino [2, 1 -a]-2,6-naphthyridine- 1,8,10(11 H)-trione
- a mixture of 1 l-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-methane-sulfonylethyl)- 3,4,5,6,12,13-hexahydro-2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8,10(llH)-trione (97 mg, 0.17 mmol), morpholine (30 mg, 0.35 mmol), and diisopropylethylamine (006 mL, 0.355 mmol)
- Step 4 ll-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13- hexahydro-2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8,10(l lH)-trione
- Step 1 l l-(3-Chloro-4-fluorobenzyl)-4-hydroxy-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-
- Step 2 1 l-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-
- Step 3 l l-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-5,6,12,13-tetrahydro- 2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,4,8,10(3H, 1 lH)-tetrone
- Step 1 l l-(3-Chloro-4-fluorobeiizyl)-4-pyriOlidin-l-yl-9-methoxy-2-methiyl-3,4,5,6,12,13- hexahydro-2H[ 1 ,4]diazocino [2, 1 -a]-2,6-naphthyridine- 1,8.10(11 H)-trione
- a mixture of 1 l-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro- 2H[l,4]diazocmo[2,l-a]-2,6-naphthyridine-l,4,8,10(3H, llH)-tetrone (30 mg, 0.06 mmol), molecular sieves (4A), pyrrolidine (23 mg, 0.32 mmol), and acetic acid (4 mg) in dichloroethane (1 mL) was heated at 80
- Step 2 11 -(3 -Chloro-4-fluoroben2yl)-9-hydroxy-2-methyl-5,6, 12, 13-tetrahydro-
- the product mixture was cooled to 0 0 C and treated successively with water (1.2 mL), 15% aq sodium hydroxide (1.2 mL), and water (3.6 mL).
- the resultant suspension was diluted with ether, and filtered with a pad of Celite. The solid filtered was washed with methylene chloride. The organic filtrates were combined and concentrated under vacuum to provide the title compound.
- Step 2 1 l-(3-Chloro-4-fluoroben2yl)-9-hydroxy-2,6-dimethyl-3,4,5,6, 12, 13-hexahydro-
- Example 29 2-ol in Example 29.
- the amino heterocycles were incorporated in the manner described in Examples 16.
- Step 3 (4R)-l l-(3-Chloro-4-fluorobenzyl)-4 5 9-dihydroxy-2 5 5 5 5-trimethyl-3,4,5 5 6,12 7 13- hexahydro-2H[l,4]diazocino[2,l-a]-2,6-naphthyridine-l,8 5 10(llH)-trione
- the title compound was prepared in a manner similar to that described in Example 10, steps 6, 8 to 1O 5 substituting N-[2-(benzyloxy)ethyl]-4- ⁇ [fe ⁇ -butyl(dimethyl)-silyl]oxy ⁇ butan-l-amine with (3R)-3-(benzyloxy)-2,2-dimethyl-4-(methylamino)butan-l-ol in step 6.
- Step 1 (2£)- 1 -(Benzyloxy)-5-(methylamino)pentan-2-ol
- Step 2 6-(3-Chloro-4-fluorobenzyl)-N-[(4S)-4,5-dil 1 ydroxypentyl]-4-methoxy-N-methyl-3,5- dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-l-carboxamide
- Step 4 ( ⁇ ⁇ -l l- ⁇ S-Chloro ⁇ -fluorobenzylJ-P-hydroxy- ⁇ -Oiydroxymethy ⁇ -methyl-
- Step 1 tert-Butyl [8-(3-Chloro-4-fluorobenzyl)-6-methoxy-3,3-dimethyl-2,5,7-trioxo-
- the reaction mixture was concentrated under vacuum. The residue was subject to column chromatography on silica gel. Collection and concentration of appropriate fractions provided the required alkylated intermediate.
- a mixture of the above material (0.49 g, 0.99 mmol), sodium hydride (71 mg, 60% dispersion; 2.96 mmol), iodomethane (0.42 g, 2.96 mmol) in anhydrous DMF (10 mL) was stirred at room temperature overnight.
- the reaction mixture was concentrated under vacuum. The residue was subject to column chromatography on silica gel.
- Step 2 2-[8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9, 10- hexahydroimidazo[2,l-a]-2,6-naphthyridin-l(5H)-yl]-N,N-dimethylacetamide
- Step 1 Methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridme-l-carboxylate
- Step 2 Methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8- hexahydro-2,6-naphthyridine- 1 -carboxylate A mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-
- Step 3 9-(3-Chloro-4-fluorobenzyl)-3-(hyrdoxymethyl)-7-methoxy-3,4,10,l l- tetrahydro[l,4]oxazino[3,4-a]-2,6-naphthyridine-l,6,8(9H)-trione
- a mixture of methyl 2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo- 2,3,5,6,7,8-hexaliydro-2,6-naphthyridine-l-carboxylate (0.20 g, 0.46 mmol), N-methylmorpholine N- oxide (67 mg, 0.58 mmol), water (0.2 mL), and osmium tetroxide (0.75 mL, 0.08 M in t-butanol) in acetone (1 mL) was stirred at room temperature overnight.
- Step 4 9-(3-Chloro-4-fluorobenzyl)-7-hydroxy-3-(acetyloxymethyl)-3,4,10,l 1- tetrahydro[l,4]oxazino[3,4-a]-2,6-naphthyridine4,6,8(9H)-trione
- a mixture of 9-(3-chloro-4-fluorobenzyl)-3-(hyrdoxymethyl)-7-methoxy-3,4,10,l 1- tetrahydro[l,4]oxazino[3,4-a]-2,6-na ⁇ hthyridine-l,6,8(9H)-trione 50 mg, 0.11 mmol
- 33% hydrogen bromide in acetic acid 0.1 g
- acetic acid 1 mL
- an oral composition of a compound of this invention 50 mg of compound of Example 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
- Encapsulated oral compositions containing any one of the compounds of Examples 2 to 64 can be similarly prepared.
- Assays for the strand transfer activity of integrase were conducted in accordance with WO 02/30930 for recombinant integrase.
- Representative compounds of the present invention exhibit inhibition of strand transfer activity in this assay.
- the compounds of Examples 1 to 64 were tested in the integrase assay and found to have IC50 values of less than about 1 micromolar. Further description on conducting the assay using preassembled complexes is found in
- 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.
- Representative compounds of the present invention that were tested in the spread assay (see Example 67) were examined for cytotoxicity up to a concentration of 10 micromolar, and no cytotoxicity was exhibited. In particular, the compounds set forth in Examples 1 to 64 exhibited no cytotoxicity at concentrations up to 10 micromolar.
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Abstract
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Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2006244424A AU2006244424B2 (en) | 2005-05-10 | 2006-05-05 | HIV integrase inhibitors |
JP2008511195A JP4982482B2 (en) | 2005-05-10 | 2006-05-05 | HIV integrase inhibitor |
EP06759135.4A EP1881825B1 (en) | 2005-05-10 | 2006-05-05 | Hiv integrase inhibitors |
US11/920,032 US7741315B2 (en) | 2005-05-10 | 2006-05-05 | HIV integrase inhibitors |
CA2607151A CA2607151C (en) | 2005-05-10 | 2006-05-05 | Hiv integrase inhibitors |
US12/760,638 US7968564B2 (en) | 2005-05-10 | 2010-04-15 | HIV integrase inhibitors |
US13/107,512 US8293731B2 (en) | 2005-05-10 | 2011-05-13 | HIV integrase inhibitors |
US13/606,929 US20130178468A1 (en) | 2005-05-10 | 2012-09-07 | Hiv integrase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US67943105P | 2005-05-10 | 2005-05-10 | |
US60/679,431 | 2005-05-10 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/920,032 A-371-Of-International US7741315B2 (en) | 2005-05-10 | 2006-05-05 | HIV integrase inhibitors |
US12/760,638 Division US7968564B2 (en) | 2005-05-10 | 2010-04-15 | HIV integrase inhibitors |
Publications (2)
Publication Number | Publication Date |
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WO2006121831A2 true WO2006121831A2 (en) | 2006-11-16 |
WO2006121831A3 WO2006121831A3 (en) | 2007-10-25 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/US2006/017369 WO2006121831A2 (en) | 2005-05-10 | 2006-05-05 | Hiv integrase inhibitors |
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US (4) | US7741315B2 (en) |
EP (1) | EP1881825B1 (en) |
JP (1) | JP4982482B2 (en) |
AU (1) | AU2006244424B2 (en) |
CA (1) | CA2607151C (en) |
TW (1) | TW200819126A (en) |
WO (1) | WO2006121831A2 (en) |
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WO2008048538A1 (en) * | 2006-10-18 | 2008-04-24 | Merck & Co., Inc. | Hiv integrase inhibitors |
US7598264B2 (en) | 2004-03-09 | 2009-10-06 | Merck & Co., Inc. | HIV integrase inhibitors |
US7619086B2 (en) | 2004-03-09 | 2009-11-17 | Merck & Co., Inc. | HIV integrase inhibitors |
US7763630B2 (en) | 2007-06-06 | 2010-07-27 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US7893055B2 (en) | 2006-06-28 | 2011-02-22 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US7897593B2 (en) | 2006-05-30 | 2011-03-01 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US7897592B2 (en) | 2005-11-15 | 2011-03-01 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US7902182B2 (en) | 2005-11-16 | 2011-03-08 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8039458B2 (en) | 2005-11-17 | 2011-10-18 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8129398B2 (en) | 2008-03-19 | 2012-03-06 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8143244B2 (en) | 2009-02-26 | 2012-03-27 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US8383639B2 (en) | 2009-10-15 | 2013-02-26 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8779144B2 (en) | 2006-03-16 | 2014-07-15 | Evotec (Us) Inc. | Bicycloheteroaryl compounds as P2X7 modulators and uses thereof |
WO2014172188A2 (en) | 2013-04-16 | 2014-10-23 | Merck Sharp & Dohme Corp. | 4-pyridone derivative compounds and uses thereof as hiv integrase inhibitors |
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US7820680B2 (en) * | 2004-03-09 | 2010-10-26 | Merck & Co., Inc. | HIV integrase inhibitors |
US8283366B2 (en) | 2010-01-22 | 2012-10-09 | Ambrilia Biopharma, Inc. | Derivatives of pyridoxine for inhibiting HIV integrase |
WO2012058173A1 (en) * | 2010-10-29 | 2012-05-03 | Merck Sharp & Dohme Corp. | Hiv integrase inhibitors |
JP5767393B2 (en) | 2011-03-31 | 2015-08-19 | ファイザー・インク | New bicyclic pyridinone |
UA110688C2 (en) | 2012-09-21 | 2016-01-25 | Пфайзер Інк. | Bicyclic pirydynony |
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US6262055B1 (en) * | 1998-06-03 | 2001-07-17 | Merck & Co., Inc. | HIV integrase inhibitors |
EP1083897A4 (en) * | 1998-06-03 | 2003-01-02 | Merck & Co Inc | Hiv integrase inhibitors |
US6306891B1 (en) * | 1998-06-03 | 2001-10-23 | Merck & Co., Inc. | HIV integrase inhibitors |
US6380249B1 (en) * | 1998-06-03 | 2002-04-30 | Merck & Co., Inc. | HIV integrase inhibitors |
AU5880600A (en) * | 1999-06-25 | 2001-01-31 | Merck & Co., Inc. | 1-(aromatic- or heteroaromatic-substituted)-3-(heteroaromatic substituted)-1,3-propanediones and uses thereof |
AU1532802A (en) * | 2000-10-12 | 2002-04-22 | Merck & Co Inc | Aza- and polyaza-naphthalenyl-carboxamides useful as hiv integrase inhibitors |
US6841558B2 (en) * | 2000-10-12 | 2005-01-11 | Merck & Co., Inc. | Aza-and polyaza-naphthalenyl carboxamides useful as HIV intergrase inhibitors |
WO2002036734A2 (en) * | 2000-10-12 | 2002-05-10 | Merck & Co., Inc. | Aza-and polyaza-naphthalenyl ketones useful as hiv integrase inhibitors |
ATE430745T1 (en) * | 2000-10-12 | 2009-05-15 | Merck & Co Inc | AZA- AND POLYAZA NAPHTHALENYL CARBOXAMIDES AS INHIBITORS OF HIV INTEGRASE |
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IL161337A0 (en) * | 2001-10-26 | 2004-09-27 | Angeletti P Ist Richerche Bio | N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase |
DK1441734T3 (en) * | 2001-10-26 | 2007-06-11 | Angeletti P Ist Richerche Bio | Dihydroxypyrimidine carboxamide inhibitors and HIV integrase |
AU2003216049B2 (en) * | 2002-01-17 | 2008-07-17 | Merck Sharp & Dohme Corp. | Hydroxynaphthyridinone carboxamides useful as HIV integrase inhibitors |
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TW200510425A (en) * | 2003-08-13 | 2005-03-16 | Japan Tobacco Inc | Nitrogen-containing fused ring compound and use thereof as HIV integrase inhibitor |
EA200601654A1 (en) * | 2004-03-09 | 2007-02-27 | Мерк Энд Ко., Инк. | HIV INTEGRASE INHIBITORS |
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- 2006-05-05 US US11/920,032 patent/US7741315B2/en not_active Expired - Fee Related
- 2006-05-05 CA CA2607151A patent/CA2607151C/en not_active Expired - Fee Related
- 2006-05-05 AU AU2006244424A patent/AU2006244424B2/en not_active Ceased
- 2006-05-05 JP JP2008511195A patent/JP4982482B2/en not_active Expired - Fee Related
- 2006-05-05 WO PCT/US2006/017369 patent/WO2006121831A2/en active Application Filing
- 2006-05-05 EP EP06759135.4A patent/EP1881825B1/en not_active Not-in-force
- 2006-10-27 TW TW095139679A patent/TW200819126A/en unknown
-
2010
- 2010-04-15 US US12/760,638 patent/US7968564B2/en not_active Expired - Fee Related
-
2011
- 2011-05-13 US US13/107,512 patent/US8293731B2/en not_active Expired - Fee Related
-
2012
- 2012-09-07 US US13/606,929 patent/US20130178468A1/en not_active Abandoned
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Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
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US7598264B2 (en) | 2004-03-09 | 2009-10-06 | Merck & Co., Inc. | HIV integrase inhibitors |
US7619086B2 (en) | 2004-03-09 | 2009-11-17 | Merck & Co., Inc. | HIV integrase inhibitors |
US7897592B2 (en) | 2005-11-15 | 2011-03-01 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US7902182B2 (en) | 2005-11-16 | 2011-03-08 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8039458B2 (en) | 2005-11-17 | 2011-10-18 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8779144B2 (en) | 2006-03-16 | 2014-07-15 | Evotec (Us) Inc. | Bicycloheteroaryl compounds as P2X7 modulators and uses thereof |
US7897593B2 (en) | 2006-05-30 | 2011-03-01 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US7893055B2 (en) | 2006-06-28 | 2011-02-22 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
WO2008048538A1 (en) * | 2006-10-18 | 2008-04-24 | Merck & Co., Inc. | Hiv integrase inhibitors |
US7763630B2 (en) | 2007-06-06 | 2010-07-27 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8129398B2 (en) | 2008-03-19 | 2012-03-06 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
US8143244B2 (en) | 2009-02-26 | 2012-03-27 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US8383639B2 (en) | 2009-10-15 | 2013-02-26 | Bristol-Myers Squibb Company | HIV integrase inhibitors |
WO2014172188A2 (en) | 2013-04-16 | 2014-10-23 | Merck Sharp & Dohme Corp. | 4-pyridone derivative compounds and uses thereof as hiv integrase inhibitors |
US9493479B2 (en) | 2013-04-16 | 2016-11-15 | Merck Sharp & Dohme Corp. | Substituted pyrido[1,2-a]pyrazines as HIV integrase inhibitors |
Also Published As
Publication number | Publication date |
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AU2006244424A1 (en) | 2006-11-16 |
US8293731B2 (en) | 2012-10-23 |
JP4982482B2 (en) | 2012-07-25 |
US20100204201A1 (en) | 2010-08-12 |
AU2006244424B2 (en) | 2011-09-22 |
WO2006121831A3 (en) | 2007-10-25 |
US7741315B2 (en) | 2010-06-22 |
US20130178468A1 (en) | 2013-07-11 |
EP1881825A4 (en) | 2011-11-30 |
CA2607151C (en) | 2012-06-19 |
CA2607151A1 (en) | 2006-11-16 |
EP1881825B1 (en) | 2013-07-24 |
JP2008540529A (en) | 2008-11-20 |
EP1881825A2 (en) | 2008-01-30 |
US20110275621A1 (en) | 2011-11-10 |
TW200819126A (en) | 2008-05-01 |
US20090054399A1 (en) | 2009-02-26 |
US7968564B2 (en) | 2011-06-28 |
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