WO2014031872A2 - Inhibiteurs à petites molécules pour le traitement d'infections parasitaires - Google Patents

Inhibiteurs à petites molécules pour le traitement d'infections parasitaires Download PDF

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WO2014031872A2
WO2014031872A2 PCT/US2013/056219 US2013056219W WO2014031872A2 WO 2014031872 A2 WO2014031872 A2 WO 2014031872A2 US 2013056219 W US2013056219 W US 2013056219W WO 2014031872 A2 WO2014031872 A2 WO 2014031872A2
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substituted
alkynyl
alkyl
alkenyl
aryl
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WO2014031872A3 (fr
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Benito Munoz
Sivaraman Dandapani
Ivan T. JEWETT
Le Quement QUEMENT
Andrew Germain
Jean-Charles MARIE
Byung-Chul Suh
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Broad Institute Inc
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Broad Institute Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/18—Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/22—Eight-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • This invention relates to small molecule pharmaceutical compounds and to their uses for treatment of parasitic infections, in particular as antitrypanosomal therapeutic compounds to treat infections with protozoa, most particularly Trypanosoma cruzi.
  • Trypanosomatids are a group of kinetoplastid protozoa distinguished by having only a single flagellum. Trypanosomatids are responsible for human diseases such as South American trypanosomiasis (Chagas Disease) caused by Trypanosoma cruzi and African trypanosomiasis (Sleeping Sickness) caused by Trypanosoma brucei. These diseases are predominately diseases of the third world.
  • Chagas disease is endemic to 18 Latin American countries, with 13 million people chronically infected. Approximately 30% of chronically infected patients will suffer from irreversible damage to the heart and digestive tract leading to death.
  • Plasmodium falciparum resistance has developed to many currently available malaria treatments. SUMMARY OF THE INVENTION
  • the invention relates to a compound of Formula I or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • n 0, 1 , 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1 , 2 or 3 ;
  • q 0, 1 , 2 or 3 ;
  • u 0, 1 , 2, 3, 4, 5, 6, 7, 8 or 9;
  • Xi is C(O), C(S), S(0) 2 , CH 2 ;
  • X 2 is O, S, S(0) 2 , Rio, C(O), CH 2 ;
  • Each X 3 , X 4 , X 5 and Xe is independently selected from CRi 4 and N;
  • Ri 4 is selected from -CN, -S(0) 2 Rio, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylhydroxy, substituted alkylhydroxy, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl;
  • Cyl represents an optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl or aryl containing one, two or three rings;
  • Ri is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylhydroxy, substituted
  • each R 2 and R 3 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR 10 , -SR 10 , - R 10 Rn, -C(O)R 10 , -C(O)OR 10 , -C(O) R 10 Rn, N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3; acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
  • each R 10 and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or membered ring; and,
  • R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR 10 , -SR 10 , -NR 10 Rn, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 10 Rn, -N(R 10 )C(O)R u , CF 3 , -CN, -NO2, -N 3 ; and,
  • each Re is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR 10 , -SR 10 , -NR 10 Rn, -C(O)R 10 , -C(O)OR 10 , -C(O) R 10 Rn, N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio; alternatively two R6 groups together with the atoms to which they are attached to form an optionally substitute
  • the invention relates to a compound of Formula II or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • R 5 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -ORio, -SRio, - NR 10 Rii, -C(0)Rio, -C(O)OR 10 , -C(O)NR 10 Rn, -N(R 10 )C(O)R n , -CF 3 , -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio.
  • the invention further relates to the treatment of a parasitic infection comprising the step of administering a compound of Formula I to a subject in need thereof.
  • the invention relates to the treatment of a disease or disorder caused by Trypanosomatids comprising the step of administering a compound of Formula I to a subject in need thereof.
  • the disease or disorder is caused by Trypanosoma cruzi or Trypanosoma brucei.
  • the disease or disorder is selected from Chagas disease, sometimes referred to as South American trypanosomiasis or African trypanosomiasis.
  • the disease is Chagas disease.
  • the invention relates to a compound of Formula I or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • n 0, 1 , 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1 , 2 or 3 ;
  • q 0, 1 , 2 or 3 ;
  • u 0, 1 , 2, 3, 4, 5, 6, 7, 8 or 9;
  • Xi is C(O), C(S), S(0) 2 , CH 2 ;
  • X 2 is O, S, S(0) 2 , Rio, C(O), CH 2 ;
  • Each X 3 , X 4 , X 5 and Xe is independently selected from CRi 4 and N;
  • Ri 4 is selected from -CN, -S(0) 2 Rio, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylhydroxy, substituted alkylhydroxy, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl;
  • Cyl represents an optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl or aryl containing one, two or three rings;
  • Ri is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylhydroxy, substituted
  • each R 2 and R3 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR10, -SR 10 , -NR10R11, -C(O)R 10 , -C(O)OR 10 , -C(O) R 10 Rn, - N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
  • each R 10 and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and, R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR 10 , -SR 10 , -NR 10 Rn, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 10 Rn, -N(R 10 )C(O)R u
  • each Re is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR10, -SR 10 , -NR 10 Rn, -C(O)Ri 0 , -C(O)ORi 0 , -C(O)NRi 0 Rn, - N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3; acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio; alternatively two R6 groups together with the atoms to which they
  • the invention relates to a compound of Formula II or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • R 5 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR1 0 , -SR1 0 , - NR 10 Rii, -C(0)Rio, -C(O)OR 10 , -C(O)NR 10 Rn, -N(R 10 )C(O)R n , -CF 3 , -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio.
  • the invention relates to a compound of Formula III or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • each s and t is independently 0, 1, 2, 3, 4, 5, or 6;
  • R7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -C(0)Rio, - C(0)ORio, -C(0)NRioRii, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio.
  • the invention relates to a compound of Formula IIIA or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • w 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • Rs and R9 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -C(O)Ri 0 , -C(O)ORi 0 , -C(O)NRi 0 Rn, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio; alternatively Rs and R9 together with the atom they are attached may form an optionally substituted two, three or four membered ring.
  • the invention relates to a compound of Formula IV or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • the invention relate to a compound of Formula IVA:
  • the invention relates to a compound of Formula IVA wherein R4 is heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl.
  • the invention relates to a compound of Formula IVB, rVC, IVD, IVE or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • the invention relates to a compound of Formula V or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • n 0, 1, 2, 3 or 4;
  • d 0, 1 , 2 or 3 ;
  • y is 0, 1 , 2 or 3 ;
  • X 2 is O, S, S(0) 2 , Rio, C(O), CH 2 ;
  • Each X 3 , X 4 , X 5 and Xe is independently selected from CRi 4 and N;
  • R 4 is selected from -CN, -S(0) 2 Rio, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylhydroxy, substituted alkylhydroxy, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl;
  • Each R 3 , Ri5 and R 1 ⁇ 2 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR10, -SR10, -NR
  • each R 10 and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
  • R4 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR 10 , -SR 10 , -NR 10 Rn, -C(O)R 10 , -C(O)OR 10 , -C(O)NR 10 Rn, -N(R 10 )C(O)R u , - CF 3 , -CN, -NO2, -N 3 ; and,
  • Gi is absent, Ci-Ci2-alkyl, substituted Ci-Ci2-alkyl, C2-Ci2-alkenyl, substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl or substituted C2-Ci2-alkynyl; and, X10 is - R12R13, -OR12, -SRi2, -C(0)Ri2, -C(0)OR 12 , -C(0)NR 12 Ri 3 , - N(R 12 )C(0)R 13 , -S(0)Ri2 or S(0) 2 Ri 2;
  • each Ri 2 and Ri 3 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of R12 and Ri 3 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • the invention relates to a compound of Formula VA or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • n 0, 1, 2, 3 or 4;
  • X 2 is O, S, S(0) 2 , Rio, C(O), CH 2 ;
  • X 7 is O, S, S(0) 2 , NRio, C(O), C(O)NR 10 , C(S), C(S)NR 10 , C(R 10 )(Rn);
  • Each X 3 , X 4 , X 5 and Xe is independently selected from CRi 4 and N;
  • Ri 4 is selected from -CN, -S(0) 2 Rio, hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylhydroxy, substituted alkylhydroxy, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl;
  • Each R 3 , Ri5 and R 1 ⁇ 2 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -ORi 0 , -SRio
  • each Rio and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
  • Rn is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl
  • Gi is absent, Ci-Ci 2 -alkyl, substituted Ci-Ci 2 -alkyl, C 2 -Ci 2 -alkenyl, substituted C 2 -Ci 2 -alkenyl, C 2 -Ci 2 -alkynyl or substituted C 2 -Ci 2 -alkynyl; and, X10 is - R12R13, -OR12, -SRi2, -C(0)Ri2, -C(0)OR 12 , -C(0)NR 12 R 13 , - N(Ri 2 )C(0)Ri3, -S(0)Ri2 or S(0) 2 R 12;
  • each Ri 2 and R1 3 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Ri 2 and R1 3 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • the invention relates to a compound of Formula VI or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • y 0, 1, 2 or 3;
  • X 8 is absent, O, S, S(0) 2 , NR 10 , C(O), C(O)NR 10 , C(S), C(S)NR 10 , C(R 10 )(Rii);
  • X 7 is O, S, S(0) 2 , Rio, C(O), C(O)NR 10 , C(S), C(S)NR 10 , C(R 10 )(Rn);
  • Linker is a bivalent aliphatic, substituted aliphatic, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl group;
  • Each Ri5 and Ri 6 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -ORio, -SR 10 , -NR 10 Rn, -C(O)Ri 0 , -C(O)ORi 0 , -C(O)NRi 0 Rn, - N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio; alternatively R15 and Ri 6 together may form an
  • each Rio and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
  • Rn is selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl; and, wherein Gi is absent, Ci-Ci2-alkyl, substituted Ci-Ci2-alkyl, C2-Ci2-alkenyl, substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl or substituted C2-Ci2-alkynyl; and, Xio is - R12R13, -OR12, -SRi2, -C(0)Ri2, -C(0)OR 12 , -C(0)NR 12 Ri 3 , - N(Ri 2 )C(0)Ri3, -S(0)Ri2 or S(0) 2 Ri 2;
  • each R 12 and R 13 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of R 12 and R 13 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • the invention relates to a compound of Formula VIA or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • y 0, 1, 2 or 3;
  • r 0, 1, 2 or 3;
  • X 8 is absent, O, S, S(0) 2 , NR 10 , C(O), C(O)NR 10 , C(S), C(S)NR 10 , C(R 10 )(Rii);
  • X 7 is O, S, S(0) 2 , R10, C(O), C(O)NR 10 , C(S), C(S)NR 10 , C(R 10 )(Rn);
  • Linker is a bivalent aliphatic, substituted aliphatic, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl group;
  • Each Ri5 ; Ri 6 and Ris is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR10, -SR10, -NR10R11, -C(0)R 1 o, -C(0)OR 1 o, - C(0)NRioRii, -N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio; alternatively R 5 and Ri6 together may form an optionally substituted
  • each R 10 and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and,
  • Gi is absent, Ci-Ci2-alkyl, substituted Ci-Ci2-alkyl, C2-Ci2-alkenyl, substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl or substituted C2-Ci2-alkynyl; and, X10 is -NR12R13, -OR12, -SRi2, -C(0)Ri2, -C(0)ORi 2 , -C(0) R 12 Ri 3 , - N(R 12 )C(0)R 13 , -S(0)Ri2 or S(0) 2 Ri 2;
  • each Ri 2 and R13 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of R12 and R13 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • the invention relates to a compound of Formula VIB or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • y 0, 1, 2 or 3;
  • r 0, 1, 2 or 3;
  • e 0, 1, 2 or 3;
  • X 8 is absent, O, S, S(0) 2 , R 10 , C(O), C(O) R 10 , C(S), C(S) R 10> C(R 10 )(Rii);
  • X 7 is O, S, S(0) 2 , R10, C(O), C(O)NR 10 , C(S), C(S)NR 10 , C(R 10 )(Rn);
  • Linker is a bivalent aliphatic, substituted aliphatic, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl group;
  • Each Ri5 ; Ri 6 , Ris and R1 9 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR10, -SR10, -NR10R11, -C(O)Ri 0 , -C(O)ORi 0 , - C(0)NRioRii, -N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio; alternatively R15
  • each Rio and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • the invention relates to a compound of Formula VIC or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • the invention relates to a compound of Formula IIA or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof;
  • R 5 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -ORio, -SRio, - NR 10 Rii, -C(0)Rio, -C(O)OR 10 , -C(O)NR 10 Rn, -N(R 10 )C(O)R n , -CF 3 , -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio; alternatively two R2 groups, or an R 2 group and an R 5
  • the invention relates to a compound of Formula IIB or IIC, or a pharmaceutically acceptable ester, salt, prodrug or metabolite thereof:
  • the invention further relates to the treatment of a parasitic infection comprising the step of administering a compound of Formula I-IV to a subject in need thereof.
  • the invention relates to the treatment of a disease or disorder caused by
  • Trypanosomatids comprising the step of administering a compound of Formula I to a subject in need thereof.
  • the disease or disorder is caused by Trypanosoma cruzi or Trypanosoma brucei.
  • the disease or disorder is Chagas disease.
  • Xi is C(O). In a preferred embodiment, X 2 is O.
  • Ri is selected from Ci-Ci2-alkyl, substituted Ci-Ci2-alkyl,
  • C2-Ci2-alkenyl substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl, substituted C2-Ci2-alkynyl, Ci- Ci2-alkylhydroxy, substituted Ci-Ci2-alkylhydroxy, C2-Ci2-alkenylhydroxy, substituted C2- Ci2-alkenylhydroxy, C2-Ci2-alkynylhydroxy, substituted C2-Ci2-alkynylhydroxy, C1-C12- alkylthio, substituted Ci-Ci2-alkylthio, C2-Ci2-alkenylthio, substituted C2-Ci2-alkenylthio, C2- Ci2-alkynylthio, substituted C2-Ci2-alkynylthio, C3-C12 cycloalkyl and substituted C3-C12- cycloalkyl.
  • the invention relates to a compound of Formula I-IV wherein R 2 is selected from hydrogen, halogen, Ci-Ci2-alkyl, substituted Ci-Ci2-alkyl, C2- Ci2-alkenyl, substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl, substituted C2-Ci2-alkynyl, C5-C12 aryl, substituted C5-C12 aryl C3-C12 cycloalkyl and substituted C3-Ci2-cycloalkyl.
  • R 2 is selected from hydrogen, halogen, Ci-Ci2-alkyl, substituted Ci-Ci2-alkyl, C2- Ci2-alkenyl, substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl, substituted C2-Ci2-alkynyl, C5-C12 aryl, substituted C5-C12 aryl C3-C12 cycloalkyl and substituted C3-Ci2-cycl
  • the invention relates to a compound of Formula II wherein R5 is selected from -G1-X10;
  • Gi is absent, Ci-Ci2-alkyl, substituted Ci-Ci2-alkyl, C2-Ci2-alkenyl, substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl or substituted C2-Ci2-alkynyl; and, X10 is - R12R13, -OR12, -SRi2, -C(0)Ri2, -C(0)OR 12 , -C(0)NR 12 Ri 3 , - N(Ri 2 )C(0)Ri3, -S(0)Ri2 or S(0) 2 Ri 3 ⁇ 4
  • each R 12 and R 13 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of R 12 and R 13 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • R 12 is Q-C ⁇ -alkylaryl, substituted Q-C -alkylaryl, C 2 -
  • Ci2-alkenylaryl substituted C 2 -C 12 -alkenylaryl, C2-Ci2-alkynylaryl or substituted C 2 -C 12 - alkynylaryl.
  • R 13 is hydrogen, methyl, ethyl, propyl or isopropyl.
  • R12 is selected from Table A:
  • p 0, 1 , 2, 3, 4 or 5;
  • Rioo is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR 10 i, -SR 10 i, - R101R102, -C(O)R 10 i, -C(O)OR 10 i, -C(0)NR 10 iRio 2 , - N(Rioi)C(0)Rio2, -CF3, -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
  • each R 10 i and R1 0 2 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of R1 0 1 and R1 0 2 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • R4 is -Xn-G 2 ;
  • Ci-Ci2-alkyl substituted Ci-Ci2-alkyl, C2-Ci2-alkenyl, substituted C2-Ci2-alkenyl, C2-Ci2-alkynyl, substituted C2-Ci2-alkynyl, -NR14-, -0-, -S- -C(O)-, -C(0)0-, -C(0)NRi4-, -N(Ri 4 )C(0)-, -S(O)- or S(0) 2 -;
  • R 14 is selected from hydrogen, -CN, -S(0)2Rio, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl,
  • heteroaryl substituted heteroaryl, heterocyclic or substituted heterocyclic
  • G2 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic.
  • R4 is -Xn-G 2 wherein -Xn- is -NHC(O)-, - C(0)N(CH 3 )- -C(O)-, -C(0)0- or - H-.
  • G2 is selected from Table B:
  • t 0, 1, 2, 3, 4 or 5;
  • R103 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR 10 i, -SR 104 , -NR 104 Rio 5 , -C(O)R 104 , -C(O)OR 104 , -C(0)NR 104 Rio 5 , - N(Rio 4 )C(0)Rio5, -CF3, -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
  • each R 04 and R105 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; alternatively two R 04 and R105 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • Ri is Ci-Cs-alkyl, Ci-Cs-alkenyl or Ci-Cs-alkynyl. In a more preferred embodiment, Ri is a Ci_C4-alkyl Ci-C4-alkenyl or Ci-C4-alkynyl.
  • Ri is a Ci-C4-alkylhydroxy, substituted Ci-C4-alkylhydroxy, C 2- C4-alkenylhydroxy, substituted C2-C4-alkenylhydroxy, C2-C4-alkynylhydroxy, substituted C 2- C4-alkynylhydroxy, Ci_C4-alkylthio, substituted Ci_C4-alkylthio, C2-C4-alkenylthio, substituted C2-C4-alkenylthio, C2-C4-alkynylthio, substituted C2-C4-alkynylthio.
  • G2 is selected from Table B2:
  • t 0, 1, 2, 3, 4 or 5;
  • Rio 3 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR 10 i, -SR 104 , -NR 104 Rio 5 , -C(O)R 104 , -C(O)OR 104 , -C(0)NR 104 Rio 5 , - N(Rio 4 )C(0)Rio5, -CF3, -CN, -N0 2 , -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
  • each Ri 04 and R105 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; alternatively two Rio 4 and R105 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • Ri is selected from Table C:
  • u 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
  • each Rio 6 , R1 0 7 and Rios is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR109, -SR109, -NR109R110, -C(0)Rio9, -
  • each R109 and Rno is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two R1 09 and Rno groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7.
  • the Linker is selected from Table D:
  • t 0, 1, 2, 3, 4 or 5;
  • Rio 3 is selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, -OR 10 i, -SR 104 , -NR 104 Rio 5 , -C(O)R 104 , -C(O)OR 104 , -C(0)NR 104 Rio 5 , - N(Rio 4 )C(0)Rio5, -CF 3 , -CN, -N0 2 , -N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio or substituted alkylthio;
  • each Ri 04 and R105 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; alternatively two Rio 4 and R105 groups together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
  • X 10 is absent, O, S, S(0) 2 , NR 10 , C(O), C(O)NR 10 , C(S), C(S)NR 10 , C(R 10 )(Rii);
  • R2 0 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl -OR 10 , -SR 10 , - R 10 Rn, -C(O)R 10 , -C(O)OR 10 , -C(O) R 10 Rn, - N(Rio)C(0)Rii, -CF 3 , -CN, -N0 2 , -N 3, acyl, alkoxy, substituted alkoxy, alkylamin
  • each R 10 and Rn is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aliphatic, substituted aliphatic, aryl and substituted aryl; alternatively two of Rio and Rn together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring.
  • the invention further relates to the treatment of a parasitic infection comprising the step of administering a compound of Formula I-VI to a subject in need thereof.
  • the invention relates to the treatment of a disease or disorder caused by
  • Trypanosomatids comprising the step of administering a compound of Formula I-VI to a subject in need thereof.
  • the disease or disorder is caused by Trypanosoma cruzi or Trypanosoma brucei.
  • the disease or disorder is Chagas disease.
  • the invention relates to a compound selected from Table
  • the invention relates to a compound selected from Table
  • Table 2 includes data from repeated assays for some of the compounds listed in Table 1.
  • the invention further provides for the use of one or more compounds of the invention in the manufacture of a medicament for halting or decreasing diseases involving parasitic infections, in particular diseases or disorders related to
  • the invention relates to a method of treating parasitic infection in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention.
  • aliphatic group refers to a non-aromatic moiety that may be saturated (e.g., single bond) or contain one or more units of unsaturation, e.g., double and/or triple bonds.
  • An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted.
  • aliphatic groups include, for example,
  • polyalkoxyalkyls such as polyalkylene glycols, polyamines, and polyimines, for example.
  • Such aliphatic groups may be further substituted. It is understood that aliphatic groups may include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and substituted or unsubstituted cycloalkyl groups as described herein.
  • acyl refers to a carbonyl substituted with hydrogen, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl, or heteroaryl.
  • acyl includes groups such as (Ci-Ce) alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C3-C6)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.),
  • the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be any one of the groups described in the respective definitions.
  • the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted” or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl group may be substituted as described above in the preferred and more preferred list of substituents, respectively.
  • alkyl is intended to include both branched and straight chain, substituted or unsubstituted saturated aliphatic hydrocarbon radicals/groups having the specified number of carbons.
  • Preferred alkyl groups comprise about 1 to about 24 carbon atoms ("C1-C24").
  • Other preferred alkyl groups comprise at about 1 to about 8 carbon atoms (“Q-Cg”) such as about 1 to about 6 carbon atoms (“Ci-Ce” , or such as about 1 to about 3 carbon atoms (“Ci- C3").
  • Ci-Ce alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, w-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl radicals.
  • alkenyl refers to linear or branched radicals having at least one carbon- carbon double bond. Such radicals preferably contain from about two to about twenty-four carbon atoms ("C 2 -C 24 "). Other preferred alkenyl radicals are “lower alkenyl” radicals having two to about ten carbon atoms (“C2-C1 0 ”) such as ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred lower alkenyl radicals include 2 to about 6 carbon atoms ("C 2 - Ce”). The terms “alkenyl”, and “lower alkenyl”, embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkynyl refers to linear or branched radicals having at least one carbon- carbon triple bond. Such radicals preferably contain from about two to about twenty- four carbon atoms ("C 2 -C 24 ").
  • Other preferred alkynyl radicals are "lower alkynyl” radicals having two to about ten carbon atoms such as propargyl, 1-propynyl, 2-propynyl, 1 -butyne, 2-butynyl and 1-pentynyl.
  • Preferred lower alkynyl radicals include 2 to about 6 carbon atoms ("C 2 -C 6 ").
  • cycloalkyl refers to saturated carbocyclic radicals having three to about twelve carbon atoms (“C3-C12").
  • cycloalkyl embraces saturated carbocyclic radicals having three to about twelve carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • cycloalkenyl refers to partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called
  • cycloalkyldienyl More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • alkylene refers to a divalent group derived from a straight chain or branched saturated hydrocarbon chain having the specified number of carbons atoms. Examples of alkylene groups include, but are not limited to, ethylene, propylene, butylene, 3-methyl-pentylene, and 5-ethyl-hexylene.
  • alkenylene denotes a divalent group derived from a straight chain or branched hydrocarbon moiety containing the specified number of carbon atoms having at least one carbon-carbon double bond.
  • Alkenylene groups include, but are not limited to, for example, ethenylene, 2-propenylene, 2-butenylene, l-methyl-2-buten-l- ylene, and the like.
  • alkynylene denotes a divalent group derived from a straight chain or branched hydrocarbon moiety containing the specified number of carbon atoms having at least one carbon-carbon triple bond.
  • Representative alkynylene groups include, but are not limited to, for example, propynylene, 1-butynylene, 2-methyl-3- hexynylene, and the like.
  • alkoxy refers to linear or branched oxy -containing radicals each having alkyl portions of one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to about ten carbon atoms and more preferably having one to about eight carbon atoms.
  • radicals examples include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl refers to alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • aryl alone or in combination, means an aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl,
  • heterocyclyl saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called “heterocyclyl”, “heterocycloalkenyl” and “heteroaryl”
  • heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • saturated heterocyclyl radicals include saturated 3 to 6-membered
  • heteromonocyclic group containing 1 to 4 nitrogen atoms e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.
  • saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms e.g., morpholinyl, etc.
  • saturated 3 to 6- membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms e.g., thiazolidinyl, etc.
  • partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
  • Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals.
  • the term "heterocycle” also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
  • heteroaryl refers to unsaturated aromatic heterocyclyl radicals.
  • heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-l,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H- 1,2,3 -triazolyl, etc.) tetrazolyl (e.g., lH-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazo
  • benzotriazolyl tetrazolopyridazinyl (e.g., tetrazolo[l,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (
  • heterocycloalkyl refers to heterocyclo-substituted alkyl radicals. More preferred heterocycloalkyl radicals are "lower heterocycloalkyl” radicals having one to six carbon atoms in the heterocyclo radical.
  • alkylthio refers to radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom.
  • Preferred alkylthio radicals have alkyl radicals of one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylthio radicals have alkyl radicals which are "lower alkylthio" radicals having one to about ten carbon atoms. Most preferred are alkylthio radicals having lower alkyl radicals of one to about eight carbon atoms. Examples of such lower alkylthio radicals include methylthio, ethylthio, propylthio, butylthio and hexylthio.
  • aralkyl or "arylalkyl” refer to aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
  • aryloxy refers to aryl radicals attached through an oxygen atom to other radicals.
  • aralkoxy or "arylalkoxy” refer to aralkyl radicals attached through an oxygen atom to other radicals.
  • aminoalkyl refers to alkyl radicals substituted with amino radicals.
  • Preferred aminoalkyl radicals have alkyl radicals having about one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More preferred aminoalkyl radicals are "lower aminoalkyl” that have alkyl radicals having one to about ten carbon atoms. Most preferred are aminoalkyl radicals having lower alkyl radicals having one to eight carbon atoms. Examples of such radicals include aminomethyl, aminoethyl, and the like.
  • alkylamino denotes amino groups which are substituted with one or two alkyl radicals.
  • Preferred alkylamino radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylamino radicals are "lower alkylamino” that have alkyl radicals having one to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl radicals having one to about eight carbon atoms.
  • Suitable lower alkylamino may be monosubstituted N- alkylamino or disubstituted ⁇ , ⁇ -alkylamino, such as N-methylamino, N-ethylamino, N,N- dimethylamino, ⁇ , ⁇ -diethylamino or the like.
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy
  • substituent may be further substituted.
  • chemical moieties that are defined and referred to throughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.) or multivalent moieties under the appropriate structural circumstances clear to those skilled in the art.
  • an "alkyl" moiety can be referred to a monovalent radical (e.g., CH 3 -CH 2 -), or in other instances, a bivalent linking moiety can be "alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH 2 -CH 2 -), which is equivalent to the term
  • alkylene alkylene
  • alkoxy alkoxy
  • alkylamino alkyloxy
  • alkylthio alkyl
  • alkyl alkylthio
  • alkyl alkyl
  • alkyl alkenyl
  • alkynyl alkynyl
  • aliphatic or "cycloalkyl”
  • halogen refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • Substituents indicated as attached through variable points of attachments can be attached to any available position on the ring structure.
  • the term "effective amount of the subject compounds,” with respect to the subject method of treatment, refers to an amount of the subject compound which, when delivered as part of desired dose regimen, brings about management of the disease or disorder to clinically acceptable standards.
  • Treatment refers to an approach for obtaining beneficial or desired clinical results in a patient.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviation of symptoms, diminishment of extent of a disease, stabilization (i.e., not worsening) of a state of disease, preventing spread (i.e., infection of others) of disease, and amelioration of the disease state (whether partial or total).
  • Combination therapy includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment).
  • the compounds of the invention can be used in combination with other pharmaceutically active compounds, preferably compounds that are able to enhance the effect of the compounds of the invention.
  • the compounds of the invention can be administered simultaneously (as a single preparation or separate
  • a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid, gel or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose;
  • cyclodextrins such as alpha- (a), beta- ( ⁇ ) and gamma- ( ⁇ ) cyclodextrins; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • Ringer's solution ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • administration is parenteral administration by injection.
  • compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable suspension or emulsion, such as INTRALIPID®, LIPOSY ® or OMEGA VEN®, or solution, in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • INTRALIPID® is an intravenous fat emulsion containing 10-30% soybean oil, 1-10% egg yolk phospholipids, 1-10% glycerin and water.
  • LIPOSYN® is also an intravenous fat emulsion containing 2-15% safflower oil, 2-15% soybean oil, 0.5-5% egg phosphatides 1-10% glycerin and water.
  • OMEGA VEN® is an emulsion for infusion containing about 5-25% fish oil, 0.5-10% egg phosphatides, 1-10% glycerin and water.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, USP and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics is known in the art (see, for example U.S. Pat. No. 5,767,068 to VanDevanter et ah, U.S. Pat. No. 5,508,269 to Smith et ah, and WO 98/43650 by Montgomery).
  • N,N- diisopropylamine (1.639 ml, 9.38 mmol) was added, the reaction mixture was cooled to 0 °C and (R)-tert-butyl 2-hydroxy-3-(isopropylamino)propylcarbamate (1.09 g, 4.69 mmol) was added, as a solution in dry DMF (42 mL). The reaction was stirred for 10 min, the ice-bath was removed and the reaction mixture was stirred for an additional 5.5 h. Cesium carbonate (1.528 g, 4.69 mmol) was added and the reaction mixture was stirred at room temperature for 10.5 h following which the reaction was heated to 60 °C for 6 h.
  • (S)-tert-butyl (3-(l,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)carbamate (S)-tert-butyl oxiran-2-ylmethylcarbamate (946 mg, 5.46 mmol), isoindoline-l,3-dione (884 mg, 6.01 mmol), and N,N,N-triethyl-2-phenylethanaminium chloride (132 mg, 0.546 mmol) were suspended in acetonitrile (1 1 ml). The reaction was heated to 70 °C with stirring for 6 days. The reaction was concentrated and partitioned between EtOAc (40 mL) and 25% sat.
  • N,N-diisopropylamine (0.977 ml, 5.59 mmol) was added to the reaction mixture followed by 2-fluoro-3-nitrobenzoyl chloride (379 mg, 1.864 mmol) dropwise as a solution in dry dicloromethane (5 mL).
  • the reaction mixture was stirred at 0 °C gradually warming to room temperature over 5 h.
  • the reaction mixture was concentrated, partitioned between (3 ⁇ 4(3 ⁇ 4 (30 mL) and water (70 mL), and extracted with CH 2 CI 2 (25 mL x 2). The combined organic layers were washed with sat.
  • the reaction was stirred for 10 min, the ice-bath was removed and the reaction was stirred for 25.5 h.
  • the reaction mixture was concentrated and partitioned between EtOAc (3 mL) and 20% sat NH 4 CI (3 mL).
  • the aqueous layer was extracted with EtOAc (2 mL x 3) and the combined organic layers were washed with water (1.5 mL), dried (MgSC ⁇ ), filtered and concentrated.
  • the crude product was purified by column chromatography on silica gel eluting with
  • the reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (22 mg, 0.106 mmol) and DMF (0.20 mL) were added and the reaction mixture was stirred for 18 h. Additional sodium triacetoxyborohydride (22 mg, 0.106 mmol) was added and the reaction mixture was stirred for 10 h. Formalin (0.11 mL, 1.41 1 mmol) and sodium triacetoxyborohydride (22.43 mg, 0.106 mmol) were added and the reaction was stirred for 36 h. The reaction mixture was diluted with DMF (0.5 mL), THF (0.5 mL) and H 2 0 (0.1 mL).
  • Triethylamine (0.956 mL, 6.86 mmol) was added to the reaction mixture.
  • the reaction mixture was cooled to 0 °C, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (394 mg, 2.057 mmol) was added and the reaction mixture was stirred for 20.5 h gradually warming to room temperature.
  • Additional EDCI (205 mg) was added to the reaction mixture and it was stirred for 7 h.
  • Additional EDCI 200 mg
  • HOBt 50 mg
  • TEA (1 mL
  • the reaction mixture was heated to 32 °C and stirred for 16 h.
  • teri-butyl (((2 ?,3 ?)-4-isopropyl-3-methyl-9-nitro-5-oxo-2,3,4,5- tetrahydrobenzo[f
  • a solution of crude tert-butyl (2R,3R)-2-(tert-butyldimethylsilyloxy)-3-(isopropylamino)butyl(methyl)carbamate (354 mg, 0.945 mmol) in dry CH2CI2 (1.5 mL) was added to a solution of 2-fluoro-3- nitrobenzoyl chloride (202 mg, 0.993 mmol) and triethylamine (395 ⁇ , 2.84 mmol) in dry CH2CI2 (9 mL) under argon at 0 °C.
  • the flask was evacuated and back-filled with nitrogen (x 3), palladium on carbon (10%; 84 mg, 0.039 mmol) was added and the flask was evacuated and back-filled with nitrogen (x 2).
  • the flask was evacuated and back-filled with hydrogen (x 3).
  • the reaction was stirred under a balloon of hydrogen at 40 °C for 13 h.
  • the reaction mixture was evacuated and back-filled with nitrogen (x 4).
  • Celite was added and the reaction mixture was stirred for 10 minutes before being filtered through a pad of Celite, rinsed with methanol and concentrated. This process was repeated thrice and the resultant crude product was dissolved in CH2CI2 (4 mL) under argon and cooled on ice.
  • 2,6-lutidine (0.275 ml, 2.364 mmol) was added followed by 4-(chlorocarbonyl)pyridinium chloride (140 mg, 0.788 mmol).
  • the reaction mixture was stirred for 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 h.
  • the reaction was diluted with CH 2 C1 2 (7 mL) and 1 M HC1 (10 ml) and extracted with CH 2 C1 2 (5 mL x 3). The combined organic layers were washed with sat. a 2 C0 3 (7 mL), water (7 mL) and sat. brine (10 mL), dried (MgSC ⁇ ), filtered and concentrated.
  • Trifluoroacetic acid 250 ⁇ , was added dropwise to the reaction mixture, stirred for 10 min, the ice bath was removed and the reaction mixture was stirred for 3 h. The reaction mixture was concentrated and dried on the high vac. A solution of 4-chlorobenzaldehyde (80 mg, 0.569 mmol) in dry DMF (1 mL) was added to a portion the resultant crude salt (54 mg, 0.109 mmol) under argon and the solution was stirred for 8 minutes. Sodium triacetoxborohydride (189 mg, 0.892 mmol) was added and the reaction was stirred for 2 h. The reaction was quenched with 1 M NaOH ( ⁇ 10 drops), stirred for 5 minutes and concentrated.
  • teri-butyl 9 -(isonicotinamido)-4'-isopropyl-5 , -oxo-4 , ,5 , -dihydro-3 , H-spiro[azetidine- 3,2'-benzo[f] [l,4]oxazepine]-l-carboxylate: Acetic acid (0.28 mL, 4.94 mmol) and sodium triacetoxyborohydride (2.01 g, 9.89 mmol) were added to a solution of tert-butyl 3- (aminomethyl)-3-hydroxyazetidine-l-carboxylate (1.00 g, 4.94 mmol) in acetone (3.63 mL, 49.40 mmol) and the reaction mixture was stirred until the starting material was consumed.
  • tert-butyl ((2S,3S)-2-((teri-butyldimethylsilyl)oxy)-4-(3-cyano-2-fluoro-iV- isopropylbenzamido)-3-methylbutyl)(methyl)carbamate In a 22 mL vial, fitted with a magnetic stirring bar, tert-butyl (25',35)-2-(ter?-butyldimethylsilyloxy)-4-(isopropylamino)-3- methylbutyl(methyl)carbamate (lg, 2.57 mmol) was dissolved in CH 2 C1 2 (3.2 mL).
  • teri-Butyl (((2S,3S)-5-isopropyl-3-methyl-6-oxo-10-(lH-tetrazol-5-yl)-3,4,5,6-tetrahydro- 2H-benzo[b] [l,5]oxazocin-2-yl)methyl)(methyl)carbamate: Behind a blast shield, a 22 mL vial, fitted with magnetic stirring bar, was charged with tert-butyl (((25,35)- 10-cyano-5- isopropyl-3-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][l,5]oxazocin-2- yl)methyl)(methyl)carbamate (182 mg, 0.453 mmol), sodium azide (442 mg, 6.80 mmol) and ammonium chloride (364 mg, 6.80 mmol).
  • the mixture was allowed to reach room temperature progressively and was stirred overnight.
  • the solution was diluted in CH 2 CI 2 (5 mL), transferred to a separatory funnel and washed with sat. NH 4 C1 solution (5 mL).
  • the phases were separated and the aqueous layer was extracted three times with CH 2 CI 2 and the combined organic layers were dried over MgS0 4 , filtered and concentrated.
  • the crude was purified by silica gel chromatography
  • tert-butyl (((2S,3S)-10-ethynyl-5-isopropyl-3-methyl-6-oxo-3,4,5,6-tetrahydro-2H- benzo[b] [l,5]oxazocin-2-yl)methyl)(methyl)carbamate: In a 22 mL vial, fitted with a magnetic stirring bar, tert-butyl (((2S,3S)-5-isopropyl-10-(methoxy(methyl)carbamoyl)-3- methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][l,5]oxazocin-2-yl)methyl)(methyl)carbamate (150mg, 0.324 mmol) was dissolved in THF (1.6 mL).
  • teri-Butyl (((2S,3S)-5-isopropyl-3-methyl-6-oxo-10-(l-(pyridin-4-yl)-lH-l,2,3-triazol-4- yl)-3,4,5,6-tetrahydro-2H-benzo[b] [l,5]oxazocin-2-yl)methyl)(methyl)carbamate: In a 22 mL vial, fitted with a magnetic stirring bar, tert-butyl (((25',35)-10-ethynyl-5-isopropyl-3- methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][l,5]oxazocin-2-yl)methyl)(methyl)carbamate (49.6 mg, 0.124 mmol) was dissolved in acetonitrile (1.2 mL).
  • Trifluoroacetic acid (106 ⁇ , 1.371 mmol) was added and the resulting mixture was stirred at room temperature. Upon complete conversion of the starting material, the volatiles were removed. The remaining oil was azeotroped with toluene several times, to yield the intermediate ammonium salt. MS (ESI) calcd for C2 3 H2 9 6 O2 [M+H] + : 421.24. Found: 421.14. In a 3 mL vial, fitted with a magnetic stirring bar, the intermediate ammonium salt was dissolved in THF (962 ⁇ ). 4-Phenoxybenzaldehyde (18.18 ⁇ ⁇ , 0.106 mmol) was added and the resulting mixture was stirred at 60 °C for 2 hours.
  • the reaction mixture was then allowed to cool to room temperature and added NaBH(OAc) 3 (30.6 mg, 0.144 mmol) in one portion.
  • the reaction mixture was stirred at room temperature overnight, and volatiles were removed.
  • the remaining oil was taken up in EtOAc (15 mL), transferred to a separation funnel and washed with sat. aqueous aHC03 (3 mL).
  • the organic layer was separated, and the aqueous phase was further extracted with EtOAc (2 x15 mL). The combined organic layers were dried over Na 2 S0 4 and the volatiles were removed.
  • (ff)-methyl 4-((teri-butoxycarbonyl)amino)-3-((teri-butyldimethylsilyl)oxy)butanoate To a 20 niL vial, equipped with a magnetic stir bar, was added a solution of (R) -methyl 4-((tert- butoxycarbonyl)amino)-3-hydroxybutanoate (1.79 g, 7.67 mmol) in DMF (12.80 mL). At 0 °C, imidazole (1.57 g, 23.02 mmol) was added, followed by TBSC1 (2.89 g, 19.18 mmol). The mixture was allowed to reach room temperature and was stirred overnight.
  • (R)-tert-butyl (2-((teri-butyldimethylsilyl)oxy)-4-(2-fluoro-iV-isopropyl-3- nitrobenzamido)butyl)carbamate To a 100 mL, round-bottomed flask, equipped with a stir bar and under nitrogen, was added a solution of (R)-tert-butyl (2-((tert- butyldimethylsilyl)oxy)-4-(isopropylamino)butyl)carbamate (161 mg, 0.45 mmol) and 2,6- lutidine (130 ⁇ , 1.12 mmol) in CH2CI2 (4.5 mL).
  • teri-butyl (((2S,3S)-5-isopropyl-3-methyl-10-nitro-6-oxo-3,4,5,6-tetrahydro-2H- benzo[b] [l,5]oxazocin-2-yl)methyl)(methyl)carbamate: To a solution of tert-butyl ((25',3R)-2-((tert-butyldimethylsilyl)oxy)-4-(isopropylamino)-3-methyl-4- oxobutyl)(methyl)carbamate (1.9 g, 4.89 mmol) and triethylamine (3.41 ml, 24.44 mmol) in CH 2 C1 2 (49 ml) was added 2-fluoro-3-nitrobenzoic acid (0.936 g, 4.6 mmol) at 0 °C.
  • the reaction mixture was warmed to room temperature and was allowed to stir at room temperature overnight. Water was added and the mixture extracted with (3 ⁇ 4(3 ⁇ 4. The combined organic extracts were dried (MgS04), filtered and concentrated. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate/hexanes to deliver the product (1.93 g, 3.47 mmol) in 71% yield.
  • teri-butyl (((2S,3S)-10-(isonicotinamido)-5-isopropyl-3-methyl-6-oxo-3,4,5,6-tetrahydro- 2H-benzo[b] [l,5]oxazocin-2-yl)methyl)(methyl)carbamate:
  • a solution of tert-butyl (((2S,35)-5-isopropyl-3-methyl- 10-nitro-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b] [ 1 ,5]oxazocin- 2-yl)methyl)(methyl)carbamate (1.40 g, 3.32 mmol) and 10% palladium on carbon in EtOAc (27.7 mL) and MeOH 5.54 mL) was stirred under a hydrogen atmosphere at room
  • Trifluoroacetic acid (0.372 ml, 4.83 mmol) was added to a solution of tert-butyl (((2S,3S - 10- (isonicotinamido)-5-isopropyl-3-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][l,5]oxazocin- 2-yl)methyl)(methyl)carbamate (0.24 g, 0.483 mmol) in CH2CI2 (4 mL) was added and stirred at room temperature. The reaction was quenched with sodium bicarbonate, extracted with ethyl acetate, dried (MgSC ⁇ ), filtered and concentrated.
  • tert-butyl (((2S,3S - 10- (isonicotinamido)-5-isopropyl-3-methyl-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][l,5]oxazocin-
  • 2-Fluoro-iV-isopropyl-iV-methyl-3-nitrobenzamide In a 250 mL round-bottomed flask fitted with a magnetic stirring bar, N-methylpropan-2-amine (0.712 ml, 6.84 mmol) and Ets (4.76 mL, 34.2 mmol) were dissolved in CH 2 CI 2 (90 mL). The resulting mixture was cooled to 0 °C. 2-Fluoro-3-nitrobenzoyl chloride (2.78 g, 13.67 mmol) was then added. The reaction mixture was warmed to room temperature and stirred overnight. Water (50 mL) was then added and the mixture was transferred to a separation funnel.
  • teri-butyl (3-(2-(isopropyl(methyl)carbamoyl)-6- nitrophenoxy)propyl)(methyl)carbamate In a flame-dried 250 mL round-bottomed flask, fitted with a magnetic stirring bar tert-butyl (3-hydroxypropyl)(methyl)carbamate (1.733 g, 9.16 mmol) was dissolved in THF (46 mL). The solution was cooled to -60 °C.
  • Trifluoroacetic acid (0.636 ml, 8.25 mmol)) was added and the resulting mixture was stirred at rt. Upon complete conversion of the starting material, the volatiles were removed. The remaining oil was transferred to a separation funnel with EtOAc (40 mL), sat. aqueous aHC03 (20 mL) and water (20 mL). The organic layer was separated and the aqueous phase was further extracted with EtOAc (5 x 40 mL). The combined organic layers were dried over MgS0 4 and the volatiles were removed in vacuo to yield the intermediate amine (300 mg, 0.780 mmol) which was used in the next step without further characterization (95% yield).
  • a high-throughput screen of small molecules was performed in duplicate in the recombinant Tulahuen strain of T. cruzi stably expressing a beta-galactosidase reporter gene. Trypomastogote-stage parasites were co-cultured with mouse fibroblast NIH/3T3 host cells, (Buckner FS, Verlinde CL, La Flamme AC, Van Voorhis WC. Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta- galactosidase. Antimicrob Agents Chemother. 1996; 40(11): 2592-2597). Signal was normalized to neutral (DMSO) controls, and a 75% inhibition cutoff was used to define a hit.
  • DMSO neutral
  • Dulbecco's modified Eagle's medium (DMEM) with Phenol Red, high glucose, with L-glutamine and sodium pyruvate was obtained from Cellgro (Mediatech Inc, Manassas, VA; Catalog no. 10-013 -CM).
  • PSG or Penicillin- streptomycin-L-glutamine (Catalog no. 10378-016), FBS-heat inactivated fetal bovine serum (FBS, Catalog no.16140-089), and 0.25% Trypsin-EDTA IX (Catalog no. 25200-072) were purchased from Gibco-Invitrogen.
  • Sterile horse serum, from donor herd (if appearance of epimastigotes) was obtained from Sigma (Catalog no. H1270).
  • Sterile, Ca++/ Mg++- free Phosphate Buffer Saline (PBS) IX was prepared in house.
  • GAL-SCREEN ® Buffer B was obtained from Applied Biosystems (Carlsbad,
  • NIH/3T3 Cell Culture NIH/3T3 cells were cultivated in DMEM supplemented with 10% FBS and 1% PSG in T 175 in 50 mL total of medium.
  • LLC-MK2 Cell Culture LLC-MK2 cells were cultivated in DMEM supplemented with 10% FBS and 1% PSG in T175 flasks in 50 mL total of medium. Cells were usually passaged twice a week at 1 :4 to 1 :8 ratios.
  • the medium was warmed up with 2% FBS/DMEM.
  • the parasites were harvested in 50- mL tubes, and spun for 10 minutes at 2200 rpm. Approximately 15 mL of media was aspirated, and the samples were incubated for 3-5 h.
  • the NIH/3T3 cells were trypsinized (refer to cell culture protocol). When the NIH/3T3 cells were detached, the cells were harvested in DMEM, 2% FBS, and 1% PSG, then counted using the Nexcelom cellometer. The cells were diluted to 166,667 cells/mL, then added to a flask and plated 5,000 cells/ 30 per well using a standard cassette multiwall drop Combi.
  • T. cruzi cells were counted, diluted to 0.166 million cells/mL, and transferred to a 2- liter flask. Then, 100 nL compounds/DMSO were pinned to each well with NIH/3T3 cells. Next, 30 ⁇ of parasites (5000 T. cruzi) were added with a standard cassette multiwall drop Combi on slow speed, and incubated for 4 days (or a minimum of 90 h). Gal-Screen was prepared, 30 ⁇ ⁇ per well were dispensed in a 384-well plate, incubated for 60 minutes, and the luminescence was read using Envision (Perkin-Elmer) at 0.1 sec/well.
  • NIH/3T3 cells For the cell toxicity assay with NIH/3T3 cells, the same materials as for T. cruzi co- culture assay were used. NIH/3T3 cells were cultivated in DMEM supplemented with 10% FBS and 1% PSG in T 175 in 50 mL total of medium.
  • NIH/3T3 cells Fifty thousand NIH/3T3 cells were seeded on sterile glass coverslips in 12-well plates and allowed to adhere overnight. Five million T cruzi parasites were added (multiplicity of infection 100: 1) and allowed to infect for 2 h in DMEM+2% FBS and PSG. Parasites were rinsed out 3X with PBS, and compounds were added at 10X their IC5 0 (as determined in AID 2044 and AID 2294). Infected cells were further incubated for 4 days and fixed for 15 min with 4% paraformaldehyde.
  • Rat skeletal myoblasts (L-6 cells) were seeded in 96-well microtitre plates at 2000 cells/well in 100 uL RPMI 1640 medium with 10% FBS and 2 mM 1-glutamine. After 24 h the medium was removed and replaced by 100 ul per well containing 5000 trypomastigote forms of T. cruzi Tulahuen strain C2C4 containing the ⁇ -galactosidase (Lac Z) gene [Buckner FS, Verlinde CL, La Flamme AC, Van Voorhis WC (1996) Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing betagalactosidase. Antimicrob Agents Chemother 40: 2592-2597].
  • Benznidazole is used as control.
  • Assays were performed in 96-well microtiter plates, each well containing 100 ul of RPMI 1640 medium supplemented with 1% L-glutamine (200mM) and 10% fetal bovine serum, and 4000 L-6 cells (a primary cell line derived from rat skeletal myoblasts). Serial drug dilutions of eleven 3-fold dilution steps covering a range from 100 to 0.002 ug/ml were prepared. After 70 hours of incubation the plates were inspected under an inverted microscope to assure growth of the controls and sterile conditions. 10 ul of Alamar Blue was then added to each well and the plates incubated for another 2 hours.
  • Podophyllotoxine is used as control.

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Abstract

L'invention concerne un composé de Formule I ou un ester, sel, promédicament ou métabolite pharmaceutiquement acceptable de celui-ci.
PCT/US2013/056219 2012-08-23 2013-08-22 Inhibiteurs à petites molécules pour le traitement d'infections parasitaires Ceased WO2014031872A2 (fr)

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US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
US12030903B2 (en) 2020-02-18 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US12054507B2 (en) 2020-02-18 2024-08-06 Gilead Sciences, Inc. Antiviral compounds
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Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2379559B1 (fr) * 2009-01-06 2017-10-25 Dana-Farber Cancer Institute, Inc. Composés pyrimido-diazépinone d'échafaudage de kinase et procédés de traitement de troubles
CA2772085A1 (fr) * 2009-08-27 2011-03-03 The U.S.A., As Represented By The Secretary, Dept. Of Health And Human S Ervices Composes qui traitent la malaria et empechent la transmission de la malaria

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US9975886B1 (en) 2017-01-23 2018-05-22 Cadent Therapeutics, Inc. Potassium channel modulators
US12357639B2 (en) 2017-09-22 2025-07-15 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
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US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
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US11459340B2 (en) 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
US11518772B2 (en) 2018-09-18 2022-12-06 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US11034705B2 (en) 2018-09-18 2021-06-15 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US12264167B2 (en) 2018-09-18 2025-04-01 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphate inhibitors
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US11993586B2 (en) 2018-10-22 2024-05-28 Novartis Ag Crystalline forms of potassium channel modulators
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