WO2009085256A1 - Composés anti-vih - Google Patents

Composés anti-vih Download PDF

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Publication number
WO2009085256A1
WO2009085256A1 PCT/US2008/013999 US2008013999W WO2009085256A1 WO 2009085256 A1 WO2009085256 A1 WO 2009085256A1 US 2008013999 W US2008013999 W US 2008013999W WO 2009085256 A1 WO2009085256 A1 WO 2009085256A1
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Prior art keywords
solvate
pharmaceutically acceptable
compound according
acceptable salt
group
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PCT/US2008/013999
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English (en)
Inventor
Theodore J. Nitz
Karl Salzwedel
Catherine Finnegan
Shirley Brunton
Stuart Flanagan
Christian Montalbetti
Thomas Stephen Coulter
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Panacos Pharmaceuticals, Inc.
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Publication of WO2009085256A1 publication Critical patent/WO2009085256A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention concerns novel pharmaceutically active thiazole derivatives, pharmaceutical compositions containing the same, their use as medicaments, and the use of thiazole derivatives for the manufacture of specific medicaments.
  • the present invention also concerns a method of treatment involving administration of thiazole derivatives.
  • novel thiazole derivatives are useful as antiretroviral agents.
  • novel thiazole derivatives are useful for the treatment of Human Immunodeficiency Virus type 1 (HIV-I).
  • HIV Human Immunodeficiency Virus
  • NNRTI non-nucleoside reverse transcriptase inhibitor
  • the HIV-I envelope is a 160 kDa glycoprotein that is cleaved to form a transmembrane subunit and a surface subunit.
  • the transmembrane subunit is termed "gp41.”
  • the surface subunit is termed "gpl20.” Crystallographic analyses of portions of both gpl20 and gp41 have contributed to the knowledge base surrounding the biochemistry of HIV-I envelope (Kwong, P. D., et al., Nature ⁇ London) 1998, 393, 648- 659 ; Chan, D. C, et al., Cell 1997, 89, 263-273; Weissenhom, W., et al., Nature 1997, 557, 426-430). It is believed that gpl20 and gp41 are held together by van der Waals forces and hydrogen bonding. The gpl20/gp41 complex is present as a trimer on the virion surface where it mediates viral attachment, fusion and entry.
  • HIV-I infection is initiated by the attachment of gpl20 to the CD4 receptor on the cell surface (Salzwedel, K., et al., J. Virol. 2000, 74, 326-333). Studies indicate that upon binding to CD4, a conformational change occurs in gpl20, resulting in the repositioning of the Vl and V2 loops of gpl20, and exposure of the gpl20 bridging sheet domain.
  • the bridging sheet, along with the V3 loop of gpl20, is then available for binding to a co- receptor on the cell surface, predominantly either CXCR4 or CCR5, (Kwong et al., 1998, Rizzuto et al., 1998, Zhang et al., 1999).
  • CXCR4 CXCR4
  • CCR5 CXCR4 co-receptor
  • CD4 binding also appears to induce conformational changes in gp41 that result in the formation of an extended intermediate structure (Furuta, R. A., et al., Nat. Struct. Biol. 1998, 5 276-279; de Rosny, E., et al., J. Virol.
  • binding of the CD4-bound gpl20 subunit to co-receptor allows the N-terminal fusion peptide of gp41 to insert into and disrupt the cellular membrane (Salzwedel et al., 2000; Finnegan, C. M., et al., J. Virol. 2002, 76, 12123-12134).
  • the gpl20 subunit then undergoes further conformational changes, perhaps induced by interaction with co-receptor, which may result in the dissociation of gpl20 from gp41.
  • These gpl20 conformational changes induce a final conformational change in gp41 in which the protein refolds into a hairpin configuration.
  • This hairpin conformation is stabilized by the binding of the C- terminal heptad repeat regions of gp41 into the outer grooves on the trimeric N-terminal heptad repeat coiled-coil intermediate structure.
  • These conformational changes culminate in the formation of a six-helix bundle structure, which promotes fusion of the viral and cellular membranes by bringing them into closer proximity. Formation of the six-helix bundle is required in order for Env-mediated fusion to occur (Eckert, D. M. and Kim, P. S., Annu. Rev. Biochem. 2001, 70, 777-810; Weiss, C. D., AIDS Rev. 2003, 5, 214-221). After a fusion pore is formed, the viral core is released into the cellular cytoplasm, thus initiating infection.
  • HIV-I entry inhibitors can generally be divided into three classifications: 1) attachment inhibitors, which inhibit virion attachment to the cell; 2) co-receptor antagonists, which interact with co-receptor to block its binding to gpl20, and 3) fusion inhibitors, which interact with Env and disrupt conformational changes that are required for fusion of the viral and cell membranes.
  • Fusion inhibitors are a relatively new class of antiretrovirals. FUZEON
  • Enfuvirtide is the first FDA approved drug that acts at a target other than reverse transcriptase or protease. Enfuvirtide inhibits Env-mediated fusion by preventing formation of the gp41 six-helix bundle structure (Matthews, T., et al., Nat. Rev. Drug Discov. 2004, 3, 215-225; Kilgore et al., 2003). While the introduction of a new class of antiretrovirals represents an advance in the medicinal arts, enfuvirtide must be injected twice daily with a specialized device. Also, some clinicians have reported non- compliance with treatment regimens due to injection site reactions associated with enfuvirtide treatment.
  • fusion inhibitor refers to inhibition of at least one of the following steps:
  • Gp 120 binding to a target cell co-receptor protein for example, the chemokine receptors CCR5 and CXCR4.
  • Non-specific attachment to the target cell via cell surface sugars such as syndecans, C-type lectin receptors ("DC-SIGN” or “CD209”), and heparin sulfate proteoglycans ("HSPG").
  • Another technical problem underlying the invention relates to the specific need for a small chemical entity fusion inhibitor.
  • Another technical problem underlying the invention relates to the specific need for an orally bioavailable fusion inhibitor.
  • Another technical problem underlying the invention relates to the specific need for a compound that inhibits viral entry by mediating the interaction of HIV ENV with a cell surface receptor, for example CD-4.
  • Another technical problem underlying the invention relates to the specific need for a compound that inhibits viral entry by mediating the interaction of HIV ENV with a co- receptor, for example either or both of the CXCR4 and CCR5 co-receptors.
  • Some compounds of the present invention include compounds of Formula I:
  • A is a 6-7 membered ring system optionally comprising one oxygen which ring system is optionally substituted with one or more Ri moieties at each carbon; each Ri is independently selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, hydroxy, hydrido, alkoxy, cyano, amido, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyl, carboxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxyalkoxyalkyl, alkoxycarbonyl, alkoxycarbonylaminoalkoxyalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylaminoalkyl, alkoxycarbony
  • R 2 , R 3 and, when present, R 3 ' are independently selected from the group consisting of hydrido, alkyl, alkoxy, arylalkyl, amino, amido, alkylsulfonylalkyl, aminoalkyl, aminoalkoxyalkyl, alkoxycarbonylamino, alkoxycarbonylalkyl, alkylthio, alkylthioalkyl, alkylsulfonyl, alkoxyalkyl, alkoxycarbonyl, alkylsulfonylamino, aminoiminomethyl, aryl, cyano, nitro, cyanoalkyl, cycloalkyl, carboxy, hydroxyiminoalkyl, halo, haloalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylaminocarbonyl, heterocyclylcarbonyl, arylalkylaminocarbonyl
  • R 2 and R 3 can be taken together to form a fused ring system optionally interrupted by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur;
  • R 4 and R 5 when present, are independently selected from the group consisting of hydrido, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, aryl, arylalkyl, or R 4 and R 5 may taken together with the nitrogen to which they are bound to form a heterocyclyl;
  • R 6 is independently selected from the group consisting of hydrido, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyanoalkyl, or haloalkyl;
  • R 7 is independently selected from the group consisting of hydrido and halo
  • X is sulfur, oxygen, NH or N-alkyl
  • Y is oxygen or alkylene
  • Z is N or CR 3 ', where R 3 1 is defined above; with the proviso that when X is sulfur, A comprises 1 oxygen.
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is: [0026] In some embodiments, Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • Formula I is:
  • R 3 ' is not present when Z is nitrogen.
  • X is sulfur. In some embodiments, X is oxygen. In some embodiments, X is NH or N-alkyl.
  • Y is oxygen
  • Y is alkylene. In some embodiments, Y is methylene. In some embodiments, Y is ethylene.
  • Z is nitrogen, hi some embodiments, Z is R 3 '.
  • A is a 6 membered heterocycle comprising an oxygen atom at the 6 position wherein A is fully saturated.
  • A is a 6 membered carbocycle wherein A is aromatic.
  • A is a 7 membered carbocycle wherein A is fully saturated.
  • A is a 6 membered carbocycle wherein A is fully saturated wherein each of the 5 and 7 positions of the bicyclic ring system that comprises A are substituted with one or two R 1 moieties independently selected from the group consisting of hydrido, alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyl, carboxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkoxyalkyl, alkoxycarbonylaminoalkoxyalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkoxyalkyl, aminoalkoxyalkyl, alkylcarbonylaminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroarylalkyl, arylcarbonylaminoalkyl, heterocyclyl, heterocyclyl
  • A comprises one R 1 moiety selected from the group consisting of hydrido, alkyl, amino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyl, carboxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, alkoxyalkoxyalkyl, alkoxycarbonylaminoalkoxyalkyl, alkoxycarbonylaminoalkyl, nitro, alkoxycarbonylalkyl, hydroxyalkoxyalkyl, aminoalkoxyalkyl, alkylcarbonylaminoalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroarylalkyl, arylcarbonylaminoalkyl, alkylsulfonyl, arylsulfonyl, alkylsulfonylaminoalkyl
  • A is a six membered ring substituted with one R 1 at the 5 position.
  • R 1 is alkyl.
  • Ri is methyl.
  • Ri is ethyl.
  • Ri is alkoxy.
  • Rj is methoxy.
  • Ri is alkoxyalkyl.
  • Ri is methoxymethyl.
  • Ri is halo.
  • Ri is fluoro.
  • Ri is chloro.
  • Ri is amino.
  • Ri is amido.
  • Ri is alkylamido.
  • Ri is methylamido.
  • Ri is ethylamido. In some embodiments, Ri is dimethylamido. In some embodiments, Ri is sulfonamido. In some embodiments, Ri is heterocyclylamido. In some embodiments, Ri is imidazolylamido. In some embodiments, Rj is alkylheterocyclylamido. In some embodiments, Ri is methylimidazolylamido. In some embodiments, Ri is nitro. In some embodiments, Ri is alkoxycarbonyl.
  • A is a six membered ring substituted with one Ri at the 7 position.
  • Ri is alkyl.
  • Ri is methyl.
  • R] is ethyl.
  • Ri is halo.
  • Ri is fluoro.
  • Ri is chloro.
  • each Ri is independently selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, hydroxy, hydrido, cyano, amido, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyl, carboxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, hydroxyalkyl, cyanoalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxyalkoxyalkyl, alkoxycarbonylaminoalkoxyalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkoxyalkyl, aminoiminoalkyl, hydroxyiminoalkyl, aminoalkoxyalkyl, alkylcarbonylaminoalkyl
  • A comprises one Ri moiety selected from the group consisting of alkoxy, halo, amido, alkylamido, sulfonamido, heterocyclylamido, and alkylheterocyclylamido.
  • R 2 and R 3 are independently selected from the group consisting of hydrido, halo, haloalkyl, hydroxyalkyl, cyano, nitro, cyanoalkyl, alkoxy, hydrosulfonyl, alkylsulfonylalkyl, aminoalkyl, aminoalkoxyalkyl, alkoxycarbonylamino, alkoxycarbonylalkyl, alkylsulfonyl, alkoxyalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroarylalkyl, arylalkyl, alkyl interrupted by one or more atoms independently selected from the group consisting of oxygen, nitrogen and sulfur; and
  • R 3 is hydrogen and R 2 is selected from the group consisting of hydrido, halo, haloalkyl, hydroxyalkyl, cyano, cyanoalkyl, alkoxy, hydrosulfonyl, alkylsulfonylalkyl, aminoalkyl, aminoalkoxyalkyl, alkoxycarbonylamino, alkoxycarbonylalkyl, alkylsulfonyl, alkoxyalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroarylalkyl, arylalkyl, alkyl interrupted by one or more atoms independently selected from the group consisting of oxygen, nitrogen and sulfur; and
  • R 2 is and R 4 and R 5 are independently selected from the group consisting of hydrido, aminoalkyl, alkyl, alkoxyalkyl, cyanoalkyl, cycloalkyl, aryl, and arylalkyl. [0058] In some embodiments, R 2 is
  • R 4 and R 5 can be taken together with the nitrogen to which they are bound to form a heterocyclyl.
  • R 2 is
  • R 4 and R 5 are independently selected from the group consisting of hydrido, methyl, ethyl, isopropyl, methoxyethyl, ethoxyethyl, ethoxymethyl, cyanoethyl, cyclopropyl, benzyl, and phenyl.
  • R 2 is
  • R 4 and R 5 are taken together with the nitrogen to which they are bound to form a heterocyclyl selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, and morpholinyl.
  • R 2 and R 3 are taken together to form a fused ring system optionally interrupted by one or more heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur.
  • R 2 , R 3 and, when present, R 3 1 are independently selected from the group consisting of hydrido, alkyl, alkoxy, arylalkyl, amino, amido, alkylsulfonylalkyl, aminoalkyl, aminoalkoxyalkyl, alkoxycarbonylamino, alkoxycarbonylalkyl, alkylsulfonyl, alkoxyalkyl, alkoxycarbonyl, alkylsulfonylamino, aminoiminomethyl, aryl, cyano, nitro, cyanoalkyl, cycloalkyl, carboxy, hydroxyiminoalkyl, halo, haloalkyl, hydroxyalkyl, heterocyclyl
  • R 2 and R 3 are independently selected from the group consisting of arylaminocarbonyl, heterocyclylcarbonyl, and arylalkylaminocarbonyl, alkylcarbonylamino.
  • R 2 and R 3 are taken together to form a fused heterocycle.
  • R 2 and R 3 are taken together to form a fused thiadiazole.
  • R 2 and R 3 are taken together to form a fused thiazole.
  • R 2 and R 3 are taken together to form a fused furan.
  • R 2 and R 3 are taken together to form a fused carbocycle.
  • R 2 and R 3 are taken together to form a fused benzyl.
  • A is a 6 membered heterocycle comprising an oxygen atom at position 6, wherein A is fully unsaturated, Z is CR 3 ', R 3 ' is hydrido, X is sulfur, Y is methylene, and R 1 is hydrido.
  • A is a 6 membered heterocycle comprising an oxygen atom at position 6, wherein A is fully unsaturated, Z is CR 3 ', X is sulfur, Y is methylene, Ri selected from the group consisting of hydrido, halo, and alkoxyalkyl, and one or more ofR 2 , R 3 , and R 3 ' is halo.
  • A is a 6 membered heterocycle comprising an oxygen atom at position 6, wherein A is fully unsaturated, Z is CR 3 ', R 3 ' is hydrido, X is sulfur, Y is methylene, Ri is selected from the group consisting of hydrido, halo, and alkoxyalkyl, and R 2 and R 3 are taken together to form a heteroaryl- or heterocyclyl-containing fused ring system.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • R 3 ' is hydrido
  • X is oxygen
  • Y is methylene
  • R 2 is halo
  • Ri is selected from the group consisting of hydrido, halo, nitro, and alkoxyalkyl.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • R 3 1 is hydrido
  • X is oxygen
  • Y is methylene
  • Ri is selected from the group consisting of hydrido, halo, nitro and alkoxyalkyl at the 5 position.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • R 3 ' is hydrido
  • X is oxygen
  • Y is methylene
  • R 2 is halo
  • Ri is selected from the group consisting of hydrido, halo, nitro, and alkoxyalkyl at the 7 position.
  • A is a 6 membered aryl ring
  • Z is N
  • X is oxygen
  • Y is methylene
  • Ri is selected from the group consisting of hydrido, halo, nitro, and alkoxyalkyl.
  • A is a 6 membered aryl ring
  • Z is N
  • X is oxygen
  • Y is methylene
  • Ri is hydrido
  • R 2 is haloalkyl, alkyl, dialkylaminocarbonyl, aminocarbonyl or cyano.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • R 3 ' is hydrido
  • X is oxygen
  • Y is methylene
  • Ri is hydrido
  • R 2 is carboxy, alkoxycarbonyl, dialkylaminocarbonyl, hydroxyalkyl, heterocyclyl, alkylaminocarbonyl, aminoiminoalkyl, aminocarbonylamido and halo.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • R 3 1 is hydrido
  • X is oxygen
  • Y is ethylene
  • R 2 is hydrido or halo
  • Ri is selected from the group consisting of hydrido, halo, alkoxy and alkoxyalkyl.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • R 3 ' is hydrido
  • X is oxygen
  • Y is methylene
  • R 2 is halo
  • Ri is selected from the group consisting of hydrido, aryl, sulfonamido, alkylcarbonylamino, dialkylaminocarbonylamino, and alkoxyalkylcarbonylamino.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • R 3 ' is hydrido
  • X is oxygen
  • Y is methylene
  • Ri is selected from the group consisting of hydrido, halo, alkoxy and alkoxyalkyl
  • R 2 and R 3 are taken together to form a heteroaryl-, carbocyclyl-, aryl-, or heteroaryl-containing fused ring system.
  • A is a 6 membered aryl ring
  • Z is CR 3 '
  • X is oxygen
  • Y is methylene
  • Ri is hydrido
  • R 2 is halo or cyano
  • at least one of R 3 or R 3 ' is halo, alkoxy, or alkyl.
  • the present invention comprises a compound as defined in any embodiment described herein for use as a medicament.
  • the present invention comprises the use of a compound as defined in any embodiment described herein, for the manufacture of a medicament to treat a disease for which an HIV inhibitor is desired.
  • the present invention comprises a method of preventing, treating or delaying the onset of AIDS in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound as defined in any embodiment described herein, optionally in combination with a therapeutically effective amount of at least one HIV inhibitor selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors; HIV maturation inhibitors, and HIV fusion inhibitors.
  • HIV protease inhibitors non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors
  • HIV maturation inhibitors HIV maturation inhibitors
  • HIV fusion inhibitors selected from the group consisting of HIV protease inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitor
  • the present invention comprises a pharmaceutical composition which comprises the product prepared by combining an effective amount of (a) a compound as defined in any embodiment described herein, and (b) a pharmaceutically acceptable carrier.
  • the compounds of the present invention have utility in antiretro viral applications.
  • Exemplary uses include anti-lentiviral applications, and anti-HIV applications.
  • the treatment of HIV is a preferred use. All forms of HIV-I are potentially treatable with compounds of the present invention.
  • Compounds of the present invention have utility in treating protease inhibitor resistant HIV, reverse transcriptase inhibitor resistant HIV, and entry/fusion inhibitor resistant HIV.
  • Compounds of the present invention have utility in treating HIV groups M, N, and O.
  • Compounds of the present invention have utility in treating HIV-I, including subtypes Al, A2, B, C, D, Fl, F2, G, H, J; and circulating recombinant HIV forms.
  • Compounds of the present invention have utility in treating CCR5 tropic HIV strains as well as CXCR4 tropic HIV strains.
  • the compounds of the present invention differ from the referenced background compounds in structure, pharmacological activity, or pharmacological potency. Some compounds of the invention not only act favorably in terms of their capability to inhibit the replication of HIV-I, but also by their improved ability to inhibit the replication of mutant strains, in particular strains which have become resistant to commercially available drugs.
  • 9-BBN means 9-borabicyclo[3.3.1]nonane.
  • alkyl as used alone or within other terms such as “haloalkyl” and
  • alkylsulfonyl means an acyclic alkyl radical, linear or branched, preferably containing from 1 to about 10 carbon atoms and more preferably containing from 1 to about 6 carbon atoms.
  • Alkyl also encompasses the sub-genera of alkenes and alkynes, such as ethenyl, ethynyl, propenyl, propynyl, isopropenyl, and other linear, branched or cyclic structures having 2-10 carbon atoms.
  • Alkyl also encompasses the sub-genus of cyclic alkyl radicals containing from 3 to about 7 carbon atoms, preferably from 3 to 5 carbon atoms.
  • Such an alkyl group may optionally be substituted with one or more substituents selected from the group consisting of C]-C 6 alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and Ci-C 6 alkylamino.
  • alkyl radicals include methyl, ethyl, chloroethyl, hydroxyethyl, w-propyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, isoamyl, hexyl, octyl, cyclopropyl, cyclohexyl, cyclohexenyl, and propynyl.
  • alkoxy embraces linear or branched oxy-containing radicals each having alkyl portions of 1 to about 6 carbon atoms, preferably 1 to about 3 carbon atoms, such as a methoxy radical.
  • alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy alkyls.
  • alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • haloalkoxy radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of 1 to about 6 carbon atoms, attached to a divalent sulfur atom.
  • alkylthioalkyl embraces alkylthio radicals, attached to an alkyl group.
  • alkylthioalkyl is methylthiomethyl.
  • amido when used independently or in conjunction with other terms such as “amidoalkyl”, 'W-monoalkylamido”, 'W-monoarylamido", “N,N-dialkylamido”, 'W-alkyl-N-arylamido", "N-alkyl-N-hydroxyamido” and "N-alkyl-N-hydroxyamidoalkyl”, embraces carbonylamino radicals including radicals where the nitrogen is covalently bonded to 2 hydrogen atoms, to 1 hydrogen and 1 atom other than hydrogen, and to 2 atoms other than hydrogen.
  • amu means atomic mass unit.
  • aryl means a fully unsaturated mono- or multi-ring carbocycle.
  • radicals include substituted or unsubstituted phenyls, naphthyls, and anthracenyls.
  • aryl as used alone or within other terms, means a mono- or multi-ring aromatic ring structure containing between one and four rings wherein such rings may be attached together in a pendent manner or may be fused. Such an "aryl” group may be optionally substituted with one or more substituents such as C 1 -C 6 alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and Ci-C 6 alkylamino.
  • aryl refers to both cyclic structures consisting only of carbon (carboaryls), and cyclic structures comprising carbon and one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen (heteroaryls).
  • BOC or "Boc” means tert-butoxycarbonyl.
  • M-BU refers to normal (primary) butyl.
  • cat means catalytic.
  • carrier as used alone or within other terms, means a mono- or multi-ring ring structure consisting only of carbon containing between one and four rings wherein such rings may be attached together in a pendent manner or may be fused.
  • carrier refers to fully saturated and unsaturated ring systems as well as partially unsaturated ring systems.
  • carrier additionally encompasses spiro systems wherein one cycloalkyl ring has a carbon ring atom in common with another cycloalkyl ring.
  • carrier additionally encompasses bridged systems.
  • Illustrative examples of monocyclic, bicyclic or tricyclic saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]octanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, cyclononanyl, cyclodecanyl, decahydronapthalenyl, and tetradecahydroanthracenyl.
  • Illustrative examples of monocyclic, bicyclic or tricyclic partially saturated carbocycles include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octenyl, bicyclo[4.2.0]octenyl, cyclononenyl, cyclodecenyl, octahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, and l,2,3,4,4a,9,9a,10-octahydroanthracenyl.
  • carbocycle includes the following exemplary structures: cyc ⁇ lopropane cyclobutane cyclopentane cyclohexane eye lopentene eye lopenta- 1 ,3 -diene cycloheptane cyclooctane
  • combination therapy refers to the administration of a compound of the present invention and a secondary anti-infective or pharmaceutical agent as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” generally is not intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • one combination of the present invention comprises a reverse transcriptase inhibitor and a fusion inhibitor of the present invention administered as separate agents at the same or different times or they can be formulated as a single, co- formulated pharmaceutical composition comprising the two compounds.
  • a combination of the present invention comprises a reverse transcriptase inhibitor and a fusion inhibitor of the present invention formulated as separate pharmaceutical compositions that can be administered at the same or different time.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • one component of a particular combination may be administered by intravenous injection while the other component(s) of the combination may be administered orally.
  • the components may be administered in any therapeutically effective sequence.
  • ⁇ means chemical shift in parts per million downfield from tetramethylsilane.
  • V means density
  • DCE means 1 ,2-dichloroethane.
  • DCM dichloromethane
  • DIPEA N/Z-diisopropylethylamine
  • DMA means N.N-dimethylacetamide.
  • DME means 1 ,2-dimethoxyethane.
  • DMF N ⁇ -dimethylformamide
  • DMP Dess-Martin periodinane
  • DMSO dimethyl sulfoxide
  • DPPA diphenylphosphoryl azide
  • EC 50 means the drug concentration that results in a 50% reduction in virus replication.
  • ES electrospray ionization
  • Et means ethyl
  • halo means a halogen radical derived from fluorine, chlorine, bromine or iodine.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, polyhaloalkyl, and perhalo radicals.
  • a monohaloalkyl radical for one example, may have one atom selected from the group consisting of iodo, bromo, chloro and fluoro atoms within the radical.
  • Polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • “Perfluoroalkyl” means an alkyl radical having all hydrido radicals replaced with fluorine atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • HATU means 6>-(7-azabenzotriazol-l-yl)-N,N ⁇ V ⁇ V- tetramethyluronium hexafiuorophosphate.
  • heterocyclyl means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms is replaced by ⁇ , S, P, or O.
  • heterocycle refers to fully saturated and unsaturated ring systems as well as partially unsaturated ring systems.
  • heterocycle is intended to include all the possible isomeric forms of the heterocycle, for example, pyrrolyl comprises lH-pyrrolyl and 2H- pyrrolyl.
  • Illustrative examples of monocyclic, bicyclic or tricyclic saturated heterocycles include tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, decahydroquinolinyl, and octahydroindolyl.
  • Illustrative examples of monocyclic, bicyclic or tricyclic partially saturated heterocycles include azetyl, pyrrolinyl, imidazolinyl, pyrazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolanyl, 2,3- dihydro-l,4-benzodioxinyl, indolinyl and the like.
  • Illustrative examples of monocyclic, bicyclic or tricyclic aromatic heterocycles include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothi
  • heterocycle includes the following exemplary structures which are not depicted as radicals as each may form be attached through a covalent bond to any atom so long as appropriate valences are maintained: o ⁇ xiranyl th ⁇ ranyl azi ⁇ dinyl oxetanyl th tetany! azetidinyl
  • heteroaryl means a fully unsaturated heterocycle.
  • any of “carbocycle,” “aryl,” “heterocycle,” or “heteroaryl” the point of attachment to the molecule of interest can be at the heteroatom or elsewhere within the ring.
  • the moiety may be linked through any ring atom or through any atom of the alkyl portion so long as the resultant molecule is chemically stable.
  • the presence of charge for example when a pyridinyl radical is attached via the ring nitrogen to yield a quaternary nitrogen, does not in and of itself mean that the resultant molecule is not chemically stable.
  • the use of "carbocycle,” “aryl,” “heterocycle,” and “heteroaryl” moieties includes divalent attachment at appropriate substitutable sites.
  • hydrolysis means high performance liquid chromatography.
  • hydrido means a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical (-OH) or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH 2 -) radical.
  • IBX means o-iodoxybenzoic acid
  • IC 50 means either the drug concentration that results in inhibition of 50% of virus replication when referring to virus replication assays, or the drug concentration that results in inhibition of 50% of 6HB formation when referring to the 6HB assay.
  • L means liters
  • LAH lithium aluminum hydride
  • LC means liquid chromatography
  • ⁇ means 10 6 .
  • m in reference to an amount means 10 "3 ; the term “m” in reference to a spectral data means multiplet.
  • M means molar
  • Ms refers to mesyl, methanesulfonyl.
  • MS mass spectrometry
  • MT-2 cells refers to human T-cell leukemia cells isolated from cord blood lymphocytes and co-cultured with cells from patients with adult T-cell leukemia.
  • the MT-2 cell line was acquired from the AIDS Research and Reference Reagent Program.
  • MTBE means methyl tert-buty ⁇ ether
  • w/z means mass-to-charge ratio
  • NMO N-methylmorpholine N-oxide
  • ⁇ MP means N-methylpyrrolidinone.
  • ⁇ MR nuclear magnetic resonance
  • o-Tol means o-tolyl.
  • oxo means a doubly bonded oxygen.
  • PCC pyridinium chlorochromate
  • Ph means phenyl
  • ppm means parts per million.
  • prodrug means a chemical derivative of an active parent drug that releases the active parent drug upon spontaneous or enzymatic biotransformation.
  • prodrug includes variations or derivatives of the compounds of this invention which have groups cleavable under metabolic conditions including solvolysis or enzymatic degradation. In some embodiments of the present invention the prodrug is either pharmacologically inactive or exhibits reduced activity relevant to its active parent drug.
  • selective as referring to a particular event means that the particular event occurs with greater frequency than other potential event(s).
  • solvate means a molecular complex comprising a compound of the present invention and a proportional number of solvent molecules.
  • hydrate means a solvate where the solvent is water.
  • the solvate comprises a fractional amount of a solvent molecule per molecule of the present invention, for example, a hemisolvate.
  • the solvate comprises one solvent molecule per molecule of the present invention, for example, a monosolvate.
  • the solvate comprises two solvent molecules per molecule of the present invention, for example, a disolvate.
  • f-Bu means tertiary butyl
  • TEA means triethylamine
  • TEOF means triethylorthoformate
  • the term "TFA" means trifluoroacetic acid.
  • “Therapeutic effect” as used herein means some extent of relief of one or more of the symptoms of an HlV-related disorder.
  • a therapeutic effect refers to one or more of the following: 1) reduction in the number of infected cells; 2) reduction in the number of virions present in serum; 3) inhibition (i.e., slowing to some extent, preferably completely) the rate of HIV replication; 4) relieving or reducing to some extent one or more of the symptoms associated with HIV; and 5) relieving or reducing the side effects associated with the administration of other antiretro viral agents.
  • “Therapeutically effective amount” as used herein means the amount required to achieve a therapeutic effect.
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • TPAP means tetra-n-propylammonium perruthenate.
  • Weight percent as used herein means the weight percent of a specified ingredient based upon the total weight of all ingredients of the composition.
  • Compounds of the present invention include all regioisomers (e.g., cis and trans isomers) and stereoisomers (e.g. R and S enantiomers) of the compound of Formula I as well as racemic and diastereomeric forms of such isomers.
  • the present invention includes an enantiomeric excess of any particular stereoisomer that is described herein. Enantiomeric excesses include excesses of whereby a particular enantiomer is provided in a relative percentage of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% and 95% compared to its other enantiomer.
  • optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active base and then separation of the mixture of diastereoisomers by crystallization, followed by liberation of the optically active bases from such salts.
  • diastereoisomeric salts may be treated with an optically active acid and then separation of the mixture of diastereoisomers by crystallization, followed by liberation of the optically active acids from such salts.
  • Examples of appropriate bases are brucine, dehydroabietylamine, quinine, cinchonidine, ephedrine, ⁇ -methylbenzylamine, deoxyphedrine, 2-amino-l-butanol, and l-(l-naphthyl)ethylamine.
  • Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • a different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules.
  • the synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
  • the optically active compounds of the present invention can likewise be obtained by utilizing an optically active starting material or reagent. These isomers may be in the form of a free acid, a free base, an ester, a salt, an amide or a prodrug.
  • variable e.g. R 3 , heteroatom, X
  • the choice of a variable is independently selected in each occurrence.
  • any or all of alkyl, alkoxy, carboxamido, aryl, carbocycle, heterocyclyl, and heteroaryl radicals may be substituted at any position with a C 1 -C 6 alkyl, hydroxyl, halo, amino, alkylamino, dialkylamino, carboxy, or cyano group so long as appropriate valences are maintained.
  • Some compounds of Formula I and their respective prodrugs can exist in several tautomeric forms, including the keto-enol form and enamine-imine form and geometric isomers and mixtures thereof. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds.
  • Dosages described in this application refer to mass of the free acid equivalent of the relevant compound.
  • Illustrative dosage unit forms of the pharmaceutical compositions can typically contain about, 100, 200, 250, 300, 350, 400, 450, or 500 mg of a compound of the present invention. In some embodiments, the dosage unit form contains about 200, 300, 400, or 500 mg of a compound of the present invention.
  • the dosage unit form can be selected to accommodate the desired frequency of administration used to achieve the specified daily dosage.
  • the amount of the unit dosage form of the pharmaceutical composition that is administered and the dosage regimen for treating the condition or disorder depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the condition or disorder, the route and frequency of administration, and thus can vary widely, as is well known.
  • each unit consists of less than a therapeutically effective amount of a compound of the present invention
  • multiple dosage units each containing smaller amounts of a compound of the present invention
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the present invention further provides pharmaceutical compositions and methods of treatment comprising prodrugs of a compound of Formula I.
  • Prodrugs of this invention may be called single, double, or triple, depending on the number of biotransformation steps required to release the active parent drug, and indicating the number of functionalities present in a precursor-type form.
  • Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism.
  • Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, an ester prepared by reaction of a parent acid with a suitable alcohol, or an amide prepared by reaction of the parent acid compound with an amine, or a basic group reacted to form an acylated base derivative.
  • prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailability.
  • a compound of Formula I having one or more free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds comprising an amino acid residue, or a polypeptide chain of two or more amino acid residues which are covalently joined through peptide bonds to a free amino, hydroxy or carboxylic acid groups of compounds of the invention.
  • Amino acid residues useful in accordance with the present invention include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, 2-aminovaleric acid, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of a compound of the invention through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include compounds wherein the administered compound undergoes oxidative metabolism to produce the active species.
  • the present invention further provides a pharmaceutically acceptable salt of a compound of the present invention composition.
  • compositions of the compounds of the invention can be prepared by contacting the base forms of these compounds with a stoichiometric amount of the appropriate base or acid in an aqueous solvent, such as water, or in an organic solvent, or in a mixture of aqueous and organic solvents.
  • an aqueous solvent such as water, or in an organic solvent, or in a mixture of aqueous and organic solvents.
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • pharmaceutically acceptable salt refers to salts of the compounds of Formula I which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
  • Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 1955; 66:219, which are known to the skilled artisan.
  • acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as /7-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, />-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid
  • organic acids such as /7-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, />-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid.
  • Example of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, bromide, iodide, acetate, propionate, decanoate, formate, hydrochloride, heptanoate, propiolate, glucuronate, glutamate, salicylate, oxalate, malonate, succinate, maleate, hydroxymaleate, mandelate, mesylate, nitrate, stearate, phthalate, terephthalate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, citrate, lactate, ⁇ -hydroxybutyrate, glycolate, tartrate, hemi-tartrate, benzenesulfonate, methanesulfonate, ethanesulfonate, propanesul
  • the pharmaceutically acceptable salt is a hydrochloride salt of a compound of the present invention
  • the pharmaceutically acceptable salt is a hydrobromide salt of a compound of the present invention.
  • the pharmaceutically acceptable salt is a methanesulfonate salt of a compound of the present invention.
  • Examples of suitable base salts, hydrates, esters, or solvates of a compound of the present invention include hydroxides, carbonates, bicarbonates, alkali metal salts, and alkaline earth metal salts.
  • Bases commonly employed to form salts of the present invention include inorganic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc and organic salts made from lysine, NJ ⁇ - dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • any salt may exist as a hydrate or solvate and that such hydrates and solvates are contemplated by the present invention.
  • salts forms are included within the scope of the present invention where a chemical of the present invention contains more than one group capable of forming such a salt.
  • disalts are preferred.
  • Examples of typical mono-salt forms include, but are not limited to hydrochloride and methanesulfonate.
  • suitable multiple salt forms include, but are not limited to dihydrochloride and dimethanesulfonate.
  • the present invention also provides all pharmaceutically-acceptable isotopically labeled compounds of the present invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, for example 2 H or 3 H, carbon, for example 11 C, 1 3 C, or 14 C, chlorine, for example 36 Cl, fluorine, for example 18 F, iodine, for example 123 I or 125 I, nitrogen, for example 13 N or 15 N, oxygen, for example 15 O, 17 O, or 18 O, phosphorus, for example 32 P, and sulfur, for example 35 S.
  • Certain isotopically labeled compounds of the present invention are useful in drug or substrate tissue studies.
  • the radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with positron emitting isotopes may be useful in positron emission topography (PET) studies for examining substrate- receptor occupancy.
  • PET positron emission topography
  • Isotopically labeled compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by synthetic processes analogous to those described in the present application using appropriate isotopically labeled reagents in place of the non-labeled reagent mentioned therein.
  • Virus and cells were incubated together at 37 °C for 2-4 hours with sporadic shaking to resuspend cells. 10 mL of media (RPMI 1640 containing 10% fetal bovine serum and supplemented with 50 ⁇ g/mL gentamicin) was then added and the virus-cell coculture was incubated at 37 °C in a humidified 5% CO 2 incubator.
  • media RPMI 1640 containing 10% fetal bovine serum and supplemented with 50 ⁇ g/mL gentamicin
  • infected H9/HIV-1 RF cells were centrifuged, the supernatant was removed, and the cells were resuspended at a density of 0.3 x 10 6 cells/mL in media (RPMI 1640 containing 10% fetal bovine serum and supplemented with 50 ⁇ g/mL gentamicin).
  • Chronically infected H9/HIV-1 RF cells were used in experiments starting 12-15 days after infection and up to 40 days post-infection.
  • Indicator cells for virus infection :
  • HeLa-CD4/LTR- ⁇ -gal (MAGI) cells were propagated in Dulbecco's Modified
  • This assay determines the effect of compounds on conformational changes in HIV envelope glycoprotein (Env) that are required in order for Env to mediate the fusion of the viral and cellular membranes during virus entry and infection. Specifically, this assay measures the effect of compounds on the formation of the HIV Env six-helix bundle (6HB) structure.
  • Env HIV envelope glycoprotein
  • H9 cells chronically infected with HIV-I (H9/H ⁇ V-1 RF ) were resuspended in
  • Stain/Wash Buffer 1% bovine serum albumin, 0.1% sodium azide in phosphate-buffered saline
  • sCD4 Recombinant soluble CD4
  • Negative control wells contained no sCD4 and no test compound.
  • Positive control wells contained sCD4 but no test compound. The plate was incubated for 1 hour at 37 0 C to allow the sCD4 to bind to HIV Env and induce conformational changes in the Env protein.
  • reaction mixture is then allowed to warm to rt over the course of 4-5 h. Reaction progress is monitored by TLC or LC/MS. On completion, the reaction mixture is poured onto ice (40 vol) and the resultant aqueous suspension extracted with EtOAc (3 x 10 vol). The combined organic phases are washed with water (2 x 10 vol), brine (10 vol), dried (Na 2 SO 4 ), filtered and the filtrate coned in vacuo. Purification by column chromatography (silica gel, 20% EtOAc in heptanes) provides the desired product.
  • Dess-Martin periodinane (1.1 equiv) is added to a rapidly stirred rt suspension of the alcohol (1 equiv) in DCM (60 vol) and molecular sieves (4 A, 8-12 mesh). Reaction progress is monitored by TLC. On completion, the molecular sieves are removed by filtration and the filtrate coned in vacuo. Column chromatography (silica gel, EtOAc) provides the desired product. Alternatively, after filtration the reaction mixture is partitioned between Et 2 O (60 vol) and 1 M NaOH (60 vol) and the two phases separated. The organic phase is washed with 1 M NaOH (2 x 60 vol) and brine (60 vol), dried (MgSO 4 ), filtered and coned in vacuo to give the desired product.
  • reaction mixture is allowed to cool to rt and the resultant precipitate isolated by filtration.
  • the solid thus obtained is treated with satd NaHCO 3 (45 vol) and extracted into EtOAc (3 x 45 vol).
  • the combined EtOAc phases are dried (Na 2 SO 4 ), filtered and the filtrate coned in vacuo affording the desired product.
  • a stirred suspension of the carboxylic acid in DCM (20 vol) at rt is treated with oxalyl chloride (1.3-3.0 equiv) followed by a few drops of DMF and the reaction mixture stirred for 0.5-1 h.
  • the DCM and oxalyl chloride are evaporated and the residue redissolved in DCM (10 vol).
  • a solution of the appropriate aminothiazole (0.85-1.0 equiv) and DIPEA (1.0-1.4 equiv) in DCM (10 vol) is added to the cooled (0 0 C) reaction mixture over 5-10 min, after which time it is warmed to rt and stirred a further 2-16 h. Amide formation is monitored by LC/MS.
  • reaction mixture is diluted with satd NaHCO 3 (50 vol) and extracted into DCM (3 x 50 vol).
  • the combined DCM phases are washed with water (50 vol) and brine (50 vol), dried (Na 2 SO 4 ), filtered and coned to afford the desired product. Further purification by column chromatography (silica gel, EtOAc in heptanes) or recrystallization (DCM) is performed as necessary.
  • Ethyl ester 1 (20.7 g) is saponified in accordance with Method B to afford the title compound (17.3 g) as an off-white powder which is used as is without further purification: 1 H NMR (360 MHz, CD 3 OD, ⁇ H ) 7.68 (IH, dd), 7.50 (IH, app td), 6.99-7.07 (2H, m), 4.82 (2H, s), 2.69 (3H, s).
  • Acid 5 (42 mg, 0.26 mmol) is treated with HATU (104 mg, 0.290 mmol), DIPEA
  • Example 9 2-Chloro-3-(4-fluorophenyl)propanal (9) [0232] The diazonium salt of 4-fluoroaniline (4.32 mL, 45.0 mmol, d 1.157) is formed using NaNO 2 (3.4 g, 50 mmol) in aqueous HCl in accordance with Method J.
  • acid 5 (0.50 g, 3.1 mmol) is converted to the acid chloride via treatment with oxalyl chloride (0.80 mL, 9.3 mmol, d 1.455) and catalytic DMF (10 ⁇ L) then treated with DIPEA (0.53 mL, 3.1 mmol, d 0.742) and aminothiazole 10 (0.64 g, 3.1 mmol).
  • Ethyl ester 12 (5.5 g) is treated with diethyl oxalate (2.3 mL, 17.0 mmol, d 1.076) and NaOEt, generated in situ using EtOH (0.90 mL, 15 mmol, d 0.789) and NaH (0.68 g, 17 mmol, 60% dispersion in mineral oil) in accordance with Method F affording the title compound (6.6 g) as a caramel oil which is used as is without further purification: LC/MS t R 2.10 min; MS (ES+) m/z 315, 317 (M+H).
  • Ethyl ester 15 (79 mg, 0.35 mmol) is hydrolyzed in accordance with Method I affording the title compound (67 mg) as an off-white powder; LC/MS t R 1.82 min; 1 H NMR (360 MHz, CD 3 OD, ⁇ H ) 8.51 (IH, s), 7.99 (IH, dd), 7.42 (IH, dd), 7.34 (IH, t).
  • acid 16 (67 mg, 0.34 mmol) is converted to the acid chloride via treatment with oxalyl chloride (42 ⁇ L, 0.48 mmol, d 1.455) and catalytic DMF (5 ⁇ L) then treated with DIPEA (82 ⁇ L, 0.48 mmol, d 0.742) and aminothiazole 10 (71 mg, 0.34 mmol).
  • Ethyl ester 20 (12.0 g) is hydrolyzed in accordance with Method B providing the title compound (6.70 g) as a dark red oil: LC/MS t R 1.44 min; 1 H NMR (360 MHz, DMSO-J 6 , ⁇ H ) 12.44 (IH, br s), 8.34-8.39 (2H, m), 7.35 (IH, dd), 5.05 (2H, s), 2.66 (3H, s).
  • Aldehyde 23 (0.450 g, 2.35 mmol) is treated with KH 2 PO 4 (0.96 g, 7.05 mmol), 2- methyl-2-butene (1.74 mL, 16.5 mmol, d 0.662) and NaClO 2 (0.70 g, 7.76 mmol) in accordance with Method E.
  • the diazonium salt of 4-fluoroaniline (0.95 mL, 10 mmol, d 1.157) is formed using NaNO 2 (0.76 g, 11 mmol) in aqueous HCl in accordance with Method J.
  • the salt thus formed is treated directly with methyl vinyl ketone (0.81 mL, 10 mmol, d 0.864), CuCl 2 -H 2 O (0.51 g, 3.0 mmol) and MgO (10 mg, 0.25 mmol) as detailed in Method J affording the crude ⁇ -chloroketone (1.6 g) as a brown oil.
  • ⁇ -Chloroaldehyde 29 (13.3 g) is reacted with thiourea (6.10 g, 79.8 mmol) in accordance with Method K providing the title compound (2.70 g) on filtration of the cooled (rt) reaction mixture as a light brown solid: LC/MS t R 1.15 min; MS (ES+) m/z 249 (M+H), 290. Reduction of the filtrate in vacuo followed by trituration of the residue with DCM (15 mL) afforded a second batch of the title compound (1.80 g) as a light brown solid.
  • Acid 5 (45 mg, 0.28 mmol) is treated with HATU (106 mg, 0.280 mmol), DIPEA
  • the diazonium salt of amine 36 (1.5 g, 6.60 mmol) is formed using NaNO 2 (0.50 g, 7.30 mmol) in 1,4-dioxane and aqueous HCl, then treated directly with 50% aqueous H 3 PO 2 in accordance with Method V.
  • Ethyl ester 37 (0.52 g, 2.45 mmol) is h " ydrolyzed in accordance with Method W providing the title compound (0.40 g) as a white powder: LC/MS tR 1.48 min; MS (ES+) m/z 185 (M+H), 226; 1 H NMR (400 MHz, CDCl 3 , ⁇ H ) 8.14 (IH, s), 4.82 (2H, s), 3.98 (2H, t), 3.04 (2H, app tt).
  • acid 38 (0.40 g, 2.2 mmol) is converted to the acid chloride via treatment with oxalyl chloride (0.56 mL, 6.5 mmol, d 1.455) and catalytic DMF (10 ⁇ L), then treated with DIPEA (0.38 mL, 2.2 mmol, d 0.742) and aminothiazole 10 (0.46 g, 2.2 mmol) to afford the title compound (0.65 g) as an off-white solid: LC/MS /R 2.18 min; MS (ES+) m/z 375 (M+H); 1 H NMR (250 MHz, CDCl 3 , ⁇ H ) 7.82 (IH, s), 7.20 (2H, dd), 7.00 (2H, t), 6.83 (IH, s), 4.84 (2H, s), 4.03 (2H, s), 3.97 (2H, t), 3.07 (2H, t).
  • acid 38 (122 mg, 0.660 mmol) is converted to the acid chloride via treatment with oxalyl chloride (0.17 mL, 2.0 mmol, d 1.455) and catalytic DMF (5 ⁇ L), and then treated with DIPEA (0.14 mL, 0.78 mmol, d 0.742) and aminothiazole 41 (120 mg, 0.56 mmol) providing the title compound (0.10 g) after column chromatography (silica gel, 60-70% EtOAc in heptanes) as an off-white solid: LC/MS t R 2.16 min; MS (ES+) m/z 382 (M+H); 1 H NMR (250 MHz, DMSO-c?
  • the diazonium salt of amine 45 (1.10 g, 4.60 mmol) is formed using NaNO 2 (0.35 g, 5.1 mmol) in 1,4-dioxane and aqueous HCl, then treated directly with 50% aqueous H 3 PO 2 in accordance with Method V.
  • Ethyl ester 46 (0.25 g, 1. " 11 mmol) is hydrolyzed in accordance with Method W providing the title compound (0.13 g) as a white powder: 1 H NMR (250 MHz, CD 3 OD, ⁇ H ) 8.08 (IH, s), 4.73-4.90 (2H, obs m), 3.69-3.85 (IH, m), 3.08 (IH, ddd), 2.56 (IH, app ddt), 1.35 (3H, d).
  • Example 50 2-Amino-3,4-dihydro-2//-thieno[2,3-£]pyran-3-carboxylic Acid Ethyl Ester (51) and 2-Amino-6,7-dihydro-4/7-thieno[3,2-c]pyraii-3-carboxylic Acid Ethyl Ester (52)
  • the diazonium salt of amine 51 (50 mg, 0.22 mmol) is formed using NaNO 2 (18 mg, 0.26 mmol) in EtOH (3 mL) and H 2 SO 4 (80 mg) at -8 0 C for 1 h, then slowly warmed to 50 0 C. After nitrogen evolution has ceased, the mixture is cooled to rt, poured into satd NaHCO 3 , and extracted with EtOAc. The organic phase is dried (Na 2 SO 4 ), filtered, and coned in vacuo.
  • Ethyl ester 53 (22 mg) is hydrolyzed in accordance with Method W providing the title compound (20 mg) as a white powder.
  • acid 54 (20 mg, 0.11 mmol) is converted to the acid chloride via treatment with oxalyl chloride (20 mg, 0.15 mmol, d 1.455) then treated with DIPEA (20 mg, 0.15 mmol) and aminothiazole 10 (22 mg, 0.11 mmol) to afford the title compound (21 mg) after silica gel chromatography (2: 1 EtOAc in heptane): LC/MS /R 2.34 min; MS (ES+) m/z 375 (M+H); 1 H NMR (250 MHz, CDCl 3 , ⁇ H ) 7.25, (s, IH), 7.21 (m, 3H), 7.02 (m, 2H), 6.93 (br s, IH), 4.30 (app t, 2H), 4.06 (s, 2H), 2.92 (app t, 2H), 2.04 (m, 2H).
  • the diazonium salt of amine 52 (42 mg, 0.18 mmol) is formed using NaNO 2 (15 mg, 0.22 mmol) in 1,4-dioxane (2 mL) and 6 N HCl (1 mL) at -12 °C for 1 h, then treated directly with 50% aqueous H 3 PO 2 in accordance with Method V providing the title compound (22 mg) as a colorless oil.
  • Ethyl ester 58 is hydrolyzed in accordance with Method W providing the title compound (30 mg) as a white powder.
  • benzofuran-3-carboxylic acid 5 (500 mg, 3.09 mmol) is converted to the acid chloride via treatment with oxalyl chloride (0.80 mL, 9.3 mmol, d 1.455) and catalytic DMF (5 ⁇ L), and then treated with DIPEA (0.50 mL, 3.1 mmol, d 0.742) and aminothiazole 41 (663 mg, 3.08 mmol) affording the title compound (455 mg) as a light brown powder: LC/MS t ⁇ 2.32 min; MS (ES+) m/z 360 (M+H); 1 H NMR (400 MHz, DMSO-J 6 , ⁇ H ) 8.96 (IH, s), 8.13 (app dd, IH), 7.83 (d, 2H), 7.71 (m, IH), 7.53 (d, 2H), 7.43 (m, 2H), 7.39 (s, IH), 4.25 (s, 2H
  • ⁇ -Chloroaldehyde 72 (14.8 g) is reacted with thiourea (7.1 g, 94 mmol) in accordance with Method K. On completion, the reaction mixture is allowed to cool to it and basified with NH 4 OH and extracted into EtOAc (3 x 100 mL). The combined organic phases are washed with brine, dried (Na 2 SO 4 ), filtered, and coned in vacuo. The residue is partitioned between DCM and 1.2 M HCl. The aqueous phase is washed with EtOAc, basified with 4 M NaOH, and extracted into EtOAc (3 x 50 mL).
  • nitroarene 74 (1.00 g, 2.64 mmol) is dissolved into cone HCl (15 mL) and chilled to 0 0 C, after which SnCl 2 (2.4 g, 11 mmol) is added. The ice bath is removed and the mixture warmed to rt, then to 80 °C for 30 min. The cooled rt reaction mixture is diluted with water and basified with 2 M NaOH and filtered. The solid obtained is washed with water and slurried in THF and filtered.
  • the sulfonamide 77 is isolated as a white solid by using the procedure described in Example 69 employing ethylsulfonyl chloride as the derivatizing agent: LC/MS tR 4.40 min; MS (ES+) m/z 442 (M+H); 1 H NMR (400 MHz, DMSO-J 6 , ⁇ H ) 9.72 (s, IH), 8.94 (s, IH), 8.10 (app dd, IH), 7.68 (m, IH), 7.40 (m, 2H), 7.30 (s, IH), 7.24 (d, 2H), 7.15 (d, 2H), 4.05 (s 2H), 3.04 (q, 2H), 1.17 (t, 3H).
  • Acetamide 81 can be prepared using the procedure described in Example 73 using acetyl chloride as the acylating agent: LC/MS t R 4.26 min; MS (ES+) m/z 410 (M+H); 1 H NMR (360 MHz, CD 3 OD, ⁇ H ) 8.62 (s, IH), 8.34 (s, IH), 7.67 (d, IH), 7.57 (d, IH), 7.35 (m, 2H), 7.26 (br s, IH), 7.10 (m, 2H), 4.17 (s, 2H), 2.20 (s, 3H).
  • Example 75 N-[5-(4-Fluorophenyl)methyl-2-thiazolyl]-5-[[(methylamino)carbonyl]amino]- 3-benzofurancarboxamide (82)
  • Urea 82 can be prepared using the procedure described in Example 70: LC/MS IR
  • the amide 84 is prepared from 3-benzofurancarboxylic acid 5 and thiazolamine 83 using the procedure described in Method R: LC/MS t R 4.64 min; MS (ES+) m/z 361 (M+H); 1H NMR (360 MHz, CD 3 OD, ⁇ H ) 8.73 (d, IH), 8.65 (s, IH), 8.20 (app ddd, IH), 7.97 (app dd, IH), 7.88 (app dd, IH), 7.64 (app ddd, IH), 7.50-7.40 (m, 2H), 7.37 (s, IH), 4.35 (s, 2H).
  • Amide 86 is prepared from acid 85 and dimethylamine hydrochloride using the procedure described in Method R: LC/MS t ⁇ 4.00 min; MS (ES+) m/z 407 (M+H); 1 H NMR (360 MHz, CDCl 3 , ⁇ H ) 10.69 (br s, IH), 8.42 (s, IH), 8.22 (s, IH), 8.04 (m, IH), 7.58-7.51 (m, 3H), 7.35 (m, 2H), 7.00 (s, IH), 4.07 (s, 2H), 3.07 (s, 3H), 3.03 (s, 3H).
  • the following species comprise some representative species of the present invention.
  • activity profiles for compounds having or exhibiting an IC 50 equal or less than 1.0 ⁇ M are accorded a "+++” designation; activity profiles for compounds having or exhibiting an IC 50 between 1.1 ⁇ M and 10.0 ⁇ M are accorded a "-H-" designation; and activity profiles for compounds having or exhibiting an IC 5O greater than 10.1 ⁇ M are accorded a "+” designation.
  • 6HB six-helix bundle formation

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Abstract

L'invention porte sur des dérivés de thiazole représentés par la Formule (I), dans laquelle R1, R2, R3, A, X, Y, Z, R6 et R7 sont décrits par les présentes. Ces dérivés de thiazole et les compositions pharmaceutiques comportant ces dérivés s'utilisent dans le traitement de maladies et d'états à médiation par le VIH.
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JP2012503664A (ja) * 2008-09-26 2012-02-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｃｒ１受容体拮抗薬としてのアザインダゾール化合物
CN103980257A (zh) * 2014-05-28 2014-08-13 苏州开元民生科技股份有限公司 8-硝基-2-四氮唑基-4-羰基苯并吡喃的合成方法
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US9815850B2 (en) 2016-02-05 2017-11-14 Denali Therapeutics Inc. Compounds, compositions and methods
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10562912B2 (en) 2013-06-05 2020-02-18 C&C Research Laboratories Heterocyclic derivatives and use thereof
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11072618B2 (en) 2016-12-09 2021-07-27 Denali Therapeutics Inc. Compounds, compositions and methods
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders
US11999750B2 (en) 2022-01-12 2024-06-04 Denali Therapeutics Inc. Crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-B][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

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US20060100232A1 (en) * 2004-11-11 2006-05-11 Summers Michael F Inhibitors of HIV-1 capsid formation: substituted aryl aminomethyl thiazole ureas and analogues thereof

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US20060100232A1 (en) * 2004-11-11 2006-05-11 Summers Michael F Inhibitors of HIV-1 capsid formation: substituted aryl aminomethyl thiazole ureas and analogues thereof

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JP2012503664A (ja) * 2008-09-26 2012-02-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｃｒ１受容体拮抗薬としてのアザインダゾール化合物
US9351954B2 (en) 2009-12-04 2016-05-31 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10894033B2 (en) 2009-12-04 2021-01-19 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10085968B2 (en) 2009-12-04 2018-10-02 Sunovion Pharmaceuticals Inc. Multicyclic compounds and methods of use thereof
US10562912B2 (en) 2013-06-05 2020-02-18 C&C Research Laboratories Heterocyclic derivatives and use thereof
CN103980257A (zh) * 2014-05-28 2014-08-13 苏州开元民生科技股份有限公司 8-硝基-2-四氮唑基-4-羰基苯并吡喃的合成方法
CN103980257B (zh) * 2014-05-28 2016-04-27 苏州开元民生科技股份有限公司 8-硝基-2-四氮唑基-4-羰基苯并吡喃的合成方法
US9815850B2 (en) 2016-02-05 2017-11-14 Denali Therapeutics Inc. Compounds, compositions and methods
US10131676B2 (en) 2016-02-05 2018-11-20 Denali Therapeutics Inc. Compounds, compositions and methods
US10604535B2 (en) 2016-02-05 2020-03-31 Denali Therapeutics Inc. Compounds, compositions and methods
US9896458B2 (en) 2016-02-05 2018-02-20 Denali Therapeutics Inc. Compounds, compositions and methods
US10196403B2 (en) 2016-07-29 2019-02-05 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US10927124B2 (en) 2016-07-29 2021-02-23 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11077090B2 (en) 2016-07-29 2021-08-03 Sunovion Pharmaceuticals Inc. Compounds and compositions and uses thereof
US11958862B2 (en) 2016-07-29 2024-04-16 Sumitomo Pharma America, Inc. Compounds and compositions and uses thereof
US11072618B2 (en) 2016-12-09 2021-07-27 Denali Therapeutics Inc. Compounds, compositions and methods
US11129807B2 (en) 2017-02-16 2021-09-28 Sunovion Pharmaceuticals Inc. Methods of treating schizophrenia
US10780074B2 (en) 2017-08-02 2020-09-22 Sunovion Pharmaceuticals Inc. Compounds and uses thereof
US11491133B2 (en) 2017-08-02 2022-11-08 Sunovion Pharmaceuticals Inc. Heteroaryl-isochroman compounds and uses thereof
US10815249B2 (en) 2018-02-16 2020-10-27 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11440921B2 (en) 2018-02-16 2022-09-13 Sunovion Pharmaceuticals Inc. Salts, crystal forms, and production methods thereof
US11987591B2 (en) 2018-02-16 2024-05-21 Sumitomo Pharma America, Inc. Salts, crystal forms, and production methods thereof
US11136304B2 (en) 2019-03-14 2021-10-05 Sunovion Pharmaceuticals Inc. Salts of a heterocyclic compound and crystalline forms, processes for preparing, therapeutic uses, and pharmaceutical compositions thereof
US11738002B2 (en) 2020-04-14 2023-08-29 Sunovion Pharmaceuticals Inc. Methods of treating neurological and psychiatric disorders
US11999750B2 (en) 2022-01-12 2024-06-04 Denali Therapeutics Inc. Crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-B][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

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