WO2018009539A1 - Inhibiteurs d'hexokinase et leurs procédés d'utilisation - Google Patents

Inhibiteurs d'hexokinase et leurs procédés d'utilisation Download PDF

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WO2018009539A1
WO2018009539A1 PCT/US2017/040715 US2017040715W WO2018009539A1 WO 2018009539 A1 WO2018009539 A1 WO 2018009539A1 US 2017040715 W US2017040715 W US 2017040715W WO 2018009539 A1 WO2018009539 A1 WO 2018009539A1
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alkylene
alkyl
compound
mmol
cycloalkyl
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PCT/US2017/040715
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Robert Cart ANDREWS
Dharma Rao Polisetti
Samuel Victory
Kurt Sundermann
Tan Ren
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Vtv Therapeutics Llc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/10—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

Definitions

  • HKII inhibition provides a promising avenue for targeting such tumors by killing the cancer cells or by interrupting the pathway by which the cells metabolize glucose to obtain ATP.
  • HKII inhibition either blocks tumor growth, kills the cells, or may render the cells more susceptible to other attacks, such as natural attacks (e.g., natural human immune responses against the tumor) or treatment- based attacks (e.g., radiation therapy, administration of chemotherapeutic agents, etc.).
  • At least one small-molecule HKII inhibitor has shown promise as an antitumor agent: In preclinical studies, 3-bromopyruvate, a small-molecule HKII inhibitor, has shown some efficacy at targeting and destroying certain tumor cells. Therefore, inhibition of HKII may serve as a promising means of treating certain types of aggressive cancers in humans or other mammals.
  • the invention relates to compounds having the structure of Formula (I): (I),
  • R 1 -R 6 , R 8a , R 8b , R 9a , R 9b , Z, X 1 , and R a are as defined in the specification.
  • the invention relates to pharmaceutical compositions of a compound of Formula (I), and a pharmaceutically acceptable carrier.
  • the invention also relates to methods of treating cancer, comprising administering to a subject a compound of the invention.
  • the invention further relates to methods of inhibiting proliferation of a cancer cell comprising contacting a cancer cell with a compound of the invention.
  • the invention also provides methods of inhibiting hexokinase activity in a cell, comprising contacting a cell with a compound of the invention.
  • Figure 1 is a graft showing the effect of a hexokinase inhibitor of the invention in an A549 lung xenograft in a mouse model.
  • the invention provides substituted heterocycles and
  • compositions thereof which can be used as antitumor agents, antifungal agents, or as anti-angiogenesis inhibitors.
  • substituted compounds are useful as HKII inhibitors.
  • the invention relates to compounds having the structure of Formula (I), or a pharmaceutically acceptable salt thereof: wherein:
  • R 1 represents -G 1 -OH, -G 1 -O-R 13 , -G 1 -NH 2 , -G 1 -NH-R 13 , or -G 1 -NR 13 R 14 , alkyl, - (alkylene)-OH, -(alkylene)-O-R 11 , -(alkylene)-SH, -(alkylene)-S-R 11 , -(alkylene)- S(O)R 11 , -(alkylene)-SO2-R 11 , -(alkylene)-NH2, -(alkylene)-NH-R 11 , -(alkylene)- NR 11 R 12 , -C(O)-R 11 , -(alkylene)-C(O)-R 11 , -CO 2 H, -(alkylene)-CO 2 H, -C(O)-O- R 11 , -(alkylene)-C(O-O-R 11
  • R 2 represents -OH, -O-R 21 , -NH2, -NH-R 21 , -NR 21 R 22 , -O-C(O)-R 21 , -NH-C(O)-R 21 , - N(R 22 )-C(O)-R 21 , -NH-C(O)-O-R 21 , -N(R 22 )-C(O)-O-R 21 , -NH-C(O)-NH 2 , -NH- C(O)-NHR 21 , -NH-C(O)-NR 21 R 22 , -N(R 22 )-C(O)-NH2, -N(R 22 )-C(O)-NHR 21 , - N(R 22 )-C(O)-NR 21 R 22 , -NH-SO2-R 21 , or -N(R 22 )-SO2-R 21 ;
  • R 1 and R 2 together with the intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring;
  • R 3 represents -OH or -O-R 31 ;
  • R 4 represents -OH or -O-R 41 ;
  • R 5 represents -G 5 -OH, -G 5 -O-R 51 , -G 5 -NH 2 , -G 5 -NH-R 51 , or -G 5 -NR 51 R 52 ;
  • G 1 and G 5 each independently represent -CR b R c -,-C(O)-, or a bond;
  • Z represents O, C(O), or C(R Z1 )(R Z2 );
  • X 1 represents N or C-R 7 ;
  • R 6 represents hydrogen or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,
  • cycloalkyl alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, (cycloalkyl)alkoxy, heterocyclylalkoxy, (heterocyclyl)alkoxy, aryloxy, arylalkoxy, heteroaryloxy, or heteroarylalkoxy;
  • R 7 represents hydrogen or lower alkyl
  • R 8a and R 8b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
  • R 9a and R 9b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
  • R 11 , R 12 , R 21 , R 22 , R 81 , R 82 , R 91 , and R 92 are each independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
  • R 11 and R 12 , R 21 and R 22 , R 81 and R 82 , or R 91 and R 92 are optionally taken together to form an optionally substituted heterocyclic ring;
  • R 13 , R 14 , R 31 , R 32 , R 41 , R 42 , R 51 , and R 52 are each independently selected from alkyl
  • R 103 and R 104 independently for each occurrence represent substituted or unsubstituted
  • alkyl alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
  • R 103 and R 104 together with the nitrogen atom to which they are attached when attached to the same nitrogen atom, are optionally taken together to form an optionally substituted heterocyclic ring;
  • R a represents hydrogen, alkyl, alkoxyalkyl, acyloxyalkyl, -C(O)-O-R 105 , or -C(O)-R 105 ;
  • R 105 represents substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
  • R b and R c are each independently for each occurrence selected from H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, and alkynyl;
  • R Z1 and R Z2 each independently represent hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyalkyl, haloalkyl, alkoxy, or haloalkoxy.
  • X 1 represents N or CH. In certain preferred such embodiments, X 1 represents CH, while in alternative embodiments, X 1 represents N. In yet other embodiments, X 1 represents CR 7 , wherein R 7 represents hydrogen or lower alkyl, such as C 1 -C 6 alkyl.
  • X 1 is CR 7 , wherein R 7 represents lower alkyl, e.g., methyl, ethyl, or isopropyl.
  • Substituent R a may represent a masking moiety, e.g., in prodrug embodiments of the compound of Formula (I) or (Ia).
  • R a represents H or alkyl.
  • R a represents H, while in alternative embodiments, R a represents hydrogen, alkyl, alkoxyalkyl, acyloxyalkyl, -C(O)-O-R 105 , or -C(O)-R 105 , wherein:
  • R 105 represents substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,
  • R a represents methyl, ethyl, isopropyl, propyl, or butyl.
  • R a may be hydrogen.
  • Z represents O
  • R 1 represents alkyl, for example, methyl or ethyl. In certain embodiments, R 1 represents substituted alkyl, such as haloalkyl or hydroxyalkyl. For example, R 1 may represent hydroxymethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.
  • R 1 represents -G 1 -OH, -G 1 -O-R 13 , -G 1 -NH 2 , -G 1 -NH-R 13 , - G 1 -NR 13 R 14 , -(alkylene)-OH, -(alkylene)-O-R 11 , -(alkylene)-NH 2 , -(alkylene)-NH-R 11 , - (alkylene)-NR 11 R 12 , -CO2H, -(alkylene)-CO2H, -C(O)-O-R 11 , -(alkylene)-C(O)-O-R 11 , - (alkylene)-O-C(O)-R 11 , -C(O)-NH 2 , -(alkylene)-C(O)-NH 2 , -C(O)-NH-R 11 , -(alkylene)- C(O)-NH-R 11 , -(al
  • R 1 represents -G 1 -OH, -G 1 -O- R 13 , -G 1 -NH2, -G 1 -NH-R 13 , -G 1 -NR 13 R 14 , -(alkylene)-CO2H, -(alkylene)-C(O)-O-R 11 , or - (alkylene)-C(O)-NH 2 , such as -G 1 -OH, -G 1 -O-R 13 , -G 1 -NH 2 , -G 1 -NH-R 13 , or -G 1 -NR 13 R 14 , e.g., -G 1 -OH or -G 1 -O-R 13 .
  • G 1 represents -CH2-.
  • R 1 represents -(alkylene)-OH, or -(alkylene)-O-R 11 .
  • the alkylene group is substituted one or more times with a substituent independently selected from fluoro and chloro.
  • R 11 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from fluoro and chloro.
  • R 1 represents -CH 2 OH.
  • the alkylene group is -CH 2 - or–
  • at least one of R 6 , R 8a , R 8b , R 9a , and R 9b is not hydrogen.
  • R 3 represents -OH or -O-R 31 . In certain preferred embodiments, R 3 represents -OH.
  • R 3 represents -O-R 31 , wherein R 31 is C1-6 alkyl optionally substituted one or more times with substituents independently selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 3 represents -O-R 31 , wherein R 31 is selected from - C(O)-R 103 , -C(O)-O-R 103 , -C(O)-N(H)-R 103 , -C(O)-NR 103 R 104 , and -SO 2 -R 103 .
  • R 31 is -C(O)-R 103 .
  • R 103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 4 represents -OH or -O-R 41 .
  • R 4 represents -O-R 41 , wherein R 41 is C1-6 alkyl optionally substituted one or more times with substituents selected independently from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 4 represents -O-R 41 , wherein R 41 is selected from -C(O)- R 103 , -C(O)-O-R 103 , -C(O)-N(H)-R 103 , -C(O)-NR 103 R 104 , and -SO 2 -R 103 , preferably -C(O)- R 103 .
  • R 103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 4 represents -OH.
  • R 3 represents -O-R 31 and R 4 represents -O-R 41
  • R 31 and R 41 are both -C(O)-R 103 .
  • R 3 and R 4 may both be -OH.
  • R 5 represents -G 5 - OH or -G 5 -O-R 51 .
  • R 5 represents -G 5 -NH2, -G 5 -NH-R 51 , or -G 5 -NR 51 R 52 .
  • G 5 represents -CR b R c -.
  • R b and R c are each independently selected from H or a carbon-based substituent such as alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, or alkynyl.
  • R b and R c together with the carbon atom to which they are attached, optionally form a C3-C6 cycloalkyl.
  • G 5 can be - C(alkyl) 2 - or -CH(alkyl).
  • G 5 is -CH 2 -. In alternative embodiments, G 5 represents -C(O)-.
  • R 5 represents -CH2OH.
  • R 5 may represent -CH 2 -O-R 51 , wherein R 51 is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy.
  • R 51 can be alkyl, cycloalkyl,
  • R 51 is methyl, ethyl, or isopropyl.
  • R 5 represents -CH2-O-R 51 , wherein R 51 is selected from - C(O)-R 103 , -C(O)-O-R 103 , -C(O)-N(H)-R 103 , -C(O)-NR 103 R 104 , and -SO2-R 103 , preferably - C(O)-R 103 .
  • R 103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 5 represents -CH2-NH2.
  • R 5 represents -CH 2 NH-R 51
  • R 51 is alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 51 is methyl, ethyl, or isopropyl.
  • R 5 represents -CH2NH-R 51
  • R 51 is C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 5 represents -CH2NH-R 51 or -CH2NR 51 R 52 .
  • R 51 and R 52 are selected from alkyl, -C(O)-R 103 , -C(O)-O-R 103 , -C(O)- N(H)-R 103 , -C(O)-NR 103 R 104 , and -SO2-R 103 .
  • R 5 represents -CH2NH-R 51 , wherein R 51 is -C(O)-R 103 or -SO2-R 103 .
  • R 103 is optionally substituted alkyl, aryl, aralkyl, or heteroaryl, such as substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
  • R 103 may represent alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy.
  • R 103 represents isoxazolyl (e.g., isoxazol-5-yl), phenyl, imidazolyl (e.g., imidazol-4-yl), oxazolyl (e.g., 2-oxazolyl), or benzyl, optionally substituted at any position with one or more substituents selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy, such as isoxazol-5-yl, optionally substituted with methyl, or phenyl, optionally substituted with one or more halogens, or imidazol-4-yl optionally substituted with methyl, or oxazole-5-yl optionally substituted with methyl.
  • isoxazolyl e.g., isoxazol-5-yl
  • phenyl e
  • R 103 represents benzyl
  • R 6 is not hydrogen. In other embodiments, R 6 represents H. In certain embodiments, R 6 represents optionally substituted alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, (cycloalkyl)alkoxy, heterocyclylalkoxy, (heterocyclyl)alkoxy, aryloxy, arylalkoxy, heteroaryloxy, or heteroarylalkoxy.
  • R 6 represents substituted or unsubstituted -CH2-(1- naphthyl), -CH2-(2-naphthyl), or -CH2-(phenyl), such as unsubstituted -CH2-(1-naphthyl), - CH 2 -(2-naphthyl), or -CH 2 -(phenyl).
  • R 6 represents -CH 2 -(1-naphthyl), -CH 2 -(2-naphthyl), or - CH2-(phenyl), substituted at at any position with one or more substituents R 65 ,
  • R 65 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R 101 , -SH, -S-R 101 , -S(O)R 101 , -SO2- R 101 , -NH 2 , -NH-R 101 , -NR 101 R 102 , -C(O)-R 101 , -CO 2 H, -C(O)-O-R 101 , -O-C(O)-R 101 , O-C(O)-OR 101 , -C(O)-NH2, -C(O)-NH-R 101 , -C(O)-NR 101 R 102 , -NH-C(O)-NH2, -C(
  • R 101 and R 102 independently for each occurrence represent substituted or unsubstituted
  • alkyl alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R 65 is selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
  • R 101 and R 102 may be alkyl, optionally substituted by an amide, carboxylic acid, ester, or ketone.
  • R 6 represents alkyl, alkenyl, alkynyl, cycloalkyl
  • heteroaralkyl such as (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl, optionally substituted at any position with one or more substituents R 65 , wherein R 65 is defined above.
  • R 6 represents -CH 2 -(1-naphthyl), -CH 2 -(2-naphthyl), or - CH 2 -(phenyl), e.g., substituted at any position with one or more substituents R 65 , wherein R 65 is defined above, or wherein each occurrence of R 65 is independently selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
  • R 65 represents halo, hydroxyl, -CO2H, cyano, or optionally substituted alkyl, alkoxy, haloalkyl, haloalkoxy, - SO2-(alkyl), -C(O)-O-(alkyl), -S(alkyl), -S(haloalkyl), heteroaryl, or aryl.
  • R 6 is C 1-6 alkyl, e.g., isobutyl.
  • R 6 is (cycloalkyl)alkyl, e.g., -C 1-6 alkylene-C 3-10 cycloalkyl, where the alkylene and cycloalkyl groups are optionally substituted with one or more with substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH2-C3-10 cycloalkyl, where the cycloalkyl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is cyclohexylmethyl.
  • R 6 is (heterocyclyl)alkyl, (e.g., -C1-6 alkylene-heterocyclyl), optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -heterocyclyl, where the heterocyclyl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain such embodiments, R 6 is tetrahydropyran-4-ylmethyl.
  • R 6 is heteroaralkyl (e.g., -C1-6 alkylene-heteroaryl), optionally substituted with one or more substituents selected independently from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • substituents selected independently from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH2-heteroaryl, where the heteroaryl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -pyridyl, where the pyridyl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain such embodiments, the pyridyl group is optionally substituted with one or two chloro groups, e.g., R 6 is 2-chloro-pyridin-5- ylmethyl.
  • R 6 is–CH2-benzothiazol-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH2-benzofuran-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH2-benzothiphene-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH2-quinoxalin-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH2-benzimidazol-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is substituted or unsubstituted aralkyl (e.g., -C1-6 alkylene-aryl).
  • aralkyl may be substituted by one or more occurrences of R 65 , as defined above.
  • R 6 is -CH(CH 3 )-aryl, optionally substituted by one or more occurrences of R 65 , as defined above.
  • R 6 is -CH(CH 3 )-phenyl, where the phenyl group is optionally substituted one or more times with substituents independently selected from fluoro, chloro, methyl, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH(CH3)-phenyl.
  • R 6 is -CH 2 -aryl (e.g., -CH 2 -naphthyl), optionally substituted by one or more occurrences of R 65 , as defined above.
  • R 6 is -CH2-(2-naphthyl), -CH2-(1-naphthyl), or -CH(CH3)2- naphthyl, where the naphthyl group is optionally substituted one or more times with substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH2-(2-naphthyl), while in other embodiments, R 6 is -CH 2 -(1-naphthyl).
  • R 6 is -CH 2 -phenyl, where the phenyl group is optionally substituted one or more times with substituents selected independently from R 65 .
  • R 6 can be -CH2-phenyl, where the phenyl group is optionally substituted one or two times with substituents selected independently from the group consisting of fluoro, chloro, bromo, methyl, methoxy, -SO2-CH3, -CO2CH3, -CO2H, trifluoromethyl,
  • R 6 is 3,4-dichlorobenzyl or 2,4-dichlorobenzyl.
  • R 6 is 4-(methanesulfonyl)benzyl or 4- (trifluoromethyl)benzyl.
  • R 6 is 2-chloro-4-fluorobenzyl or 4-fluorobenzyl.
  • R 6 is 3-chloro-4-methoxy-benzyl or 4-isopropyl-benzyl.
  • R 6 is 2,4-difluorobenzyl, 4-fluorobenzyl, 3- (methoxy)benzyl, 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl, 2-chloro-4-methoxybenzyl, 4-(trifluoromethoxy)benzyl, 4-(1,2,4-triazol-1-yl)benzyl, 2,4-dimethylbenzyl, 4- (methoxycarbonyl)-benzyl, 4-(trifluoromethylsulfanyl)-benzyl, 4-(morpholin-4-ylsulfonyl)- benzyl, 2-methoxybenzyl, 4-(pyrazol-1-yl)benzyl, 2,6-dichlorobenzyl, 4-(methoxy)benzyl, benzyl, 4-cyanobenz
  • R 2 represents -OH or -O-R 21 . In certain such embodiments, R 2 represents -O-R 21 , but in more preferred embodiments, R 2 represents - OH.
  • R 21 represents optionally substituted alkyl, alkenyl, or alkynyl.
  • R 21 may be C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl, wherein each is optionally substituted one or more times with substituents selected independently from the group consisting of halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 21 represents 3,3-dimethyl-butyl, 2,2-dimethyl- propyl, 1,1-dimethyl-prop-2-ynyl, 1,1-dimethyl-but-2-ynyl, or 1,1-diethyl-prop-2-ynyl.
  • R 21 represents C 3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 21 may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 2 is -OH or -NH2, -NH-R 21 , or -NR 21 R 22 , e.g., -OH or -NH- R 21 .
  • R 2 may be -OH or -N(C1-6 alkyl)-R 21 , such as -OH or -N(CH3)-R 21 .
  • R 21 may represent optionally substituted C 1-10 alkyl, such as C 1-10 alkyl optionally substituted with halogen.
  • R 21 is C1-6 alkyl optionally substituted one or more times with substituents independently selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 21 may be methyl, ethyl, or isopropyl, preferably methyl.
  • R 2 represents is -OH or -NH-C(O)-R 21 .
  • R 2 represents -OH or -N(C 1-6 alkyl)-C(O)-R 21 .
  • R 2 may be -N(CH3)-C(O)-R 21 .
  • R 2 represents–OH, -NH-C(O)-NH2, -NH-C(O)-NHR 21 , - NH-C(O)-NR 21 R 22 , -N(R 22 )-C(O)-NH 2 , -N(R 22 )-C(O)-NHR 21 , or -N(R 22 )-C(O)-NR 21 R 22 .
  • R 2 is–OH, -NH-C(O)-O-R 21 or -N(R 22 )-C(O)-O-R 21 .
  • R 2 is -NH-C(O)-O-R 21 .
  • R 21 and R 22 independently are C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, phenyl, benzyl, wherein each is optionally substituted one or more times with substituents independently selected from halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 2 is -OH or -NR 21 R 22 , wherein R 21 and R 22 combine to form a ring selected from pyrrolidino, piperidino, piperazino, morpholino, and
  • each said ring is optionally substituted by one or more substituents independently selected from halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, and oxo.
  • R 21 and R 22 combine to form a pyrrolidino or a piperidinyl ring, where each said ring is optionally substituted by one or more substituents independently selected from halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, and dimethylamino.
  • R 1 and R 2 together with the intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring.
  • R 1 and R 2 may together form a tetrahydrofuran ring that is fused to the remainder of the molecule.
  • R 8a and R 8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR 81 , halogen, and cyano. In more particular embodiments of the invention, one or both of R 8a or R 8b may be -OR 81 , halogen, or cyano. In certain embodiments, R 8a and R 8b are each hydrogen.
  • R 8a is hydrogen. In other embodiments, R 8a is not hydrogen, e.g., -OH, -O-R 81 , cyano, or halogen.
  • R 8a is -O-R 81 or -O-C(O)R 81 .
  • R 81 is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R 81 is alkyl, e.g., methyl or ethyl.
  • R 8b is hydrogen. In other embodiments, R 8b is not hydrogen, e.g., -OH, -O-R 81 , cyano, or halogen.
  • R 8b is -O-R 81 or -O-C(O)R 81 .
  • R 81 is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R 81 is alkyl, e.g., methyl or ethyl. In other exemplary
  • R 8b is -O-benzyl
  • R 8a , R 8b , and R 9a are each hydrogen.
  • R 9a and R 9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR 91 , halogen, and cyano, preferably such that at least one of R 9a and R 9b represents -OR 91 .
  • R 91 represents alkyl.
  • one or both of R 9a or R 9b may be - OR 91 , halogen, or cyano.
  • R 9b represents -OR 91 . In certain such embodiments,
  • R 91 represents alkyl
  • R 9a and R 9b each independently represent alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, optionally substituted at any position by one or more substituents R 95 , wherein:
  • R 95 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R 101 , -SH, -S-R 101 , -S(O)R 101 , -SO 2 -R 101 , -NH 2 , -NH-R 101 , - NR 101 R 102 , -C(O)-R 101 , -CO2H, -C(O)-O-R 101 , -O-C(O)-R 101 , O-C(O)-OR 101 , -C(O)- NH2, -C(O)-NH-R 101 , -C(O)-NR 101 R 102 , -NH-C(O)-R 101 ,
  • R 101 and R 102 independently for each occurrence represent substituted or unsubstituted
  • alkyl alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R 9a is hydrogen. In other embodiments, R 9a is not hydrogen, e.g., -OH or -O-R 91 . In certain embodiments, R 9a is -O-R 91 . In certain such embodiments, R 91 is C1-4 alkyl, e.g., methyl.
  • R 9a is halogen, e.g., bromo or chloro. In certain embodiments, R 9a is C1-6 alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 9a is C2-6 alkenyl, e.g., vinyl.
  • R 9a is -C(O)-R 91 , -C(O)-NHR 91 , -S(O) 2 -R 91 ,–C(O)-O-R 91 , or–CO 2 H, wherein R 91 is -C 1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 91 can be methyl, ethyl, or isopropyl.
  • R 9a is C 3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.
  • R 9a is phenyl, optionally substituted with one or more substituents R 95 wherein:
  • R 95 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R 101 , -SH, -S-R 101 , -S(O)R 101 , -SO 2 -R 101 , -NH 2 , -NH-R 101 , - NR 101 R 102 , -C(O)-R 101 , -CO 2 H, -C(O)-O-R 101 , -O-C(O)-R 101 , O-C(O)-OR 101 , -C(O)- NH2, -C(O)-NH-R 101 , -C(O)-NR 101 R 102 , -NH-C(O)-R 101 ,
  • R 101 and R 102 independently for each occurrence represent substituted or unsubstituted
  • alkyl alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R 9a is phenyl, optionally substituted with one or more substituents R 95 , wherein each occurrence of R 95 is independently selected from chloro, fluoro, C1-6 alkyl, -O-R 91 , -CO2H, -CO2-R 91 , -S(O)2-R 91 , and hydroxyl, and R 91 is C1-C6 alkyl or C1-C6 haloalkyl.
  • R 9a is selected from furan-3-yl, pyrazol-4-yl, thiazol-5-yl, thiazol-4-yl, thiazol-2-yl, oxazol-2-yl, imidazol-2-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]thiadiazol-5-yl, optionally substituted with one or more occurrences of R 95 as described above.
  • R 95 is methyl.
  • R 9b is hydrogen.
  • R 9b is not hydrogen, e.g., -OH or -O-R 91 , such as -O-R 91 .
  • R 91 is C1-4 alkyl, e.g., methyl, ethyl, isopropyl, or n-propyl.
  • R 91 is - (CH 2 ) 2 -OCH 3 .
  • R 91 is C 3-10 cycloalkyl, e.g., cyclohexyl.
  • R 9b is halogen, e.g., bromo or chloro.
  • R 9b is C 1-6 alkyl (e.g., methyl, ethyl, or isopropyl).
  • R 9b is C 2-6 alkenyl, e.g., vinyl.
  • R 9b is -C(O)-R 91 , -C(O)-NHR 91 , -S(O)2-R 91 ,–C(O)-O-R 91 , and–CO2H.
  • R 91 is -C1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.
  • R 91 can be methyl, ethyl, or isopropyl.
  • R 9b is C 3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.
  • R 9b is phenyl, optionally substituted with one or more substituents R 95 wherein:
  • R 95 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R 101 , -SH, -S-R 101 , -S(O)R 101 , -SO2-R 101 , -NH2, -NH-R 101 , - NR 101 R 102 , -C(O)-R 101 , -CO 2 H, -C(O)-O-R 101 , -O-C(O)-R 101 , O-C(O)-OR 101 , -C(O)- NH2, -C(O)-NH-R 101 , -C(O)-NR 101 R 102 , -NH-C(O)-R 101 , -N(
  • R 101 and R 102 independently for each occurrence represent substituted or unsubstituted
  • alkyl alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R 9b is phenyl, optionally substituted with one or more substituents R 95 , wherein each occurrence of R 95 is independently selected from chloro, fluoro, C1-6 alkyl, -O-R 91 , -CO2H, -CO2-R 91 , -S(O)2-R 91 , and hydroxyl, and R 91 is C1-C6 alkyl C1-C6 haloalkyl.
  • R 9b is 4-fluorophenyl, 4-chlorophenyl, 4- (methanesulfonyl)-phenyl, 2-methoxyphenyl, cyano, or -NO 2 .
  • R 9b is heteroaryl, optionally substituted by one or more occurrences of R 95 as described above.
  • R 9b is furan-3-yl, pyrazol-4-yl, thiazol-5-yl, thiazol-4-yl, thiazol-2-yl, oxazol-2-yl, imidazol-2-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl,
  • R 95 is methyl.
  • R 9b is pyridyl (e.g., 3-pyridyl or pyridyl-4-yl), optionally substituted with one or two substituents selected independently from the group consisting of methyl and methoxy.
  • R 9b is 3-pyridyl, 6-methylpyridin-3-yl, 2-methoxypyridin- 3-yl, 2,3-dimethylpyridin-4-yl, 1H-tetrazol-5-yl, 4-methylthiazol-2-yl, 1,3,5-trimethyl-1H- pyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, pyrimidin-5-yl, or -C(S)-NH 2 .
  • At least one of R 6 , R 8a , R 8b , R 9a , and R 9b is not H.
  • compounds of the invention may be prodrugs of the compounds of Formula (I) or (Ia), e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester.
  • the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, or carboxylic acid).
  • compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. The compounds of the invention have more than one stereocenter. Consequently, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • wedged and dashed lines indicate relative stereochemistry in the compounds of Formula (I) or (Ia). In other embodiments, wedged and dashed lines indicate absolute stereochemistry in the compounds of Formula (I) or (Ia). Where no stereochemistry is indicated, the compound may be either stereoisomer or a mix of stereoisomers at the indicated position.
  • the present invention relates to methods of treating or preventing cancer with a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof.
  • the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula I).
  • An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture.
  • a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula I).
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the present invention provides a pharmaceutical preparation suitable for use in a human patient in the treatment of cancer, comprising an effective amount of any compound of Formula (I) or (Ia), and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein.
  • the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient.
  • Exemplary compounds of Formula I are depicted in the Examples.
  • the compounds in the Examples may be depicted as the free base or the conjugate acid.
  • Compounds may be isolated in either the free base form, as a salt (e.g., a hydrochloride salt) or in both forms.
  • a salt e.g., a hydrochloride salt
  • standard chemical abbreviations are sometimes used.
  • Compounds of the invention inhibit HK2 enzyme activity.
  • Compounds that inhibit HK2 enzyme activity are potentially useful in treating diseases, disorders, or conditions where inhibition of HK2 is beneficial, such as fungal infections or various cancers (e.g., tumors of the pancreas, ovary, or liver).
  • the invention provides methods of treating cancer, comprising administering to a subject a compound of Formula (I) or (Ia), e.g., in a therapeutically effective amount.
  • the cancer may be one or a variant of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS- Related Cancers (Kaposi Sarcoma and Lymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepithelioma, Pineal Par
  • CML Myelogenous Leukemia
  • CML Chronic Myeloproliferative Disorders
  • Colon Cancer Colorectal Cancer
  • Craniopharyngioma Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome)
  • Duct Bile (Extrahepatic)
  • Ductal Carcinoma In situ DCIS
  • Embryonal Tumors Central Nervous System
  • Endometrial Cancer Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (like Intraocular Melanoma, Retinoblastoma), Fibrous
  • Myelodysplastic/Myeloproliferative Neoplasms Chronic Myeloid Leukemia (CML), Acute Myelogenous Leukemia (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, Germ Cell Tumor, and Low Malignant Potential Tumor), Pancreatic Cancer (including Islet Cell Tumors),
  • Papillomatosis Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (such as Ewing Sarcoma Family of Tumors, Kaposi, Soft Tissue, Uterine), Sézary Syndrome, Skin Cancer (such as Melanoma, Merkel Cell Carcinoma, Nonmelanoma),
  • the cancer is a solid tumor.
  • the subject is generally one who has been diagnosed as having a cancerous tumor or one who has been previously treated for a cancerous tumor (e.g., where the tumor has been previously removed by surgery).
  • the cancerous tumor may be a primary tumor and/or a secondary (e.g., metastatic) tumor.
  • the solid tumor is a highly glycolytic tumor.
  • the subject is a mammal, e.g., a human.
  • the cancerous tumor comprises cancer cells of a highly glycolytic phenotype.
  • Such tumors are referred to herein as highly glycolytic tumors.
  • Highly glycolytic tumors can be located in a wide range of tissue types, including brain, colon, urogenital, lung, renal, prostate, pancreas, liver, esophagus, stomach, hematopoietic, breast, thymus, testis, ovarian, skin, bone marrow, or uterine tissues.
  • Highly glycolytic tumors are known to those of skill in the art.
  • highly glycolytic tumors are tumors that exhibit a high rate of glucose metabolism to synthesize high levels of ATP.
  • highly glycolytic tumors comprise cells that obtain at least 40% or at least 50% of their ATP from glycolysis under aerobic conditions.
  • highly glycolytic tumors comprise cells that, when contacted with an HKII inhibitor at a concentration of about 1-10 nM, or about 10-100 nM, or 100-1000 nM, or 1- 10 ⁇ M, shows a substantial decrease in its rate of ATP generation, e.g., at least a 10% decrease in its rate of ATP generation, or at least a 20% decrease in its rate of ATP generation, or at least a 25% decrease in its rate of ATP generation, or at least a 30% decrease in its rate of ATP generation, or at least a 40% decrease in its rate of ATP generation, or at least a 50% decrease in its rate of ATP generation, or at least a 60% decrease in its rate of ATP generation, or at least a 75% decrease in its rate of ATP generation.
  • an HKII inhibitor at a concentration of about 1-10 nM, or about 10-100 nM, or 100-1000 nM, or 1- 10 ⁇ M, shows a substantial decrease in its rate of ATP generation, e.g., at
  • highly glycolytic tumors comprise cells that exhibit an increased uptake of fluorine-labeled deoxyglucose (FDG) in comparison to normal cells, when such uptake is measured by positron emission tomography (PET).
  • FDG fluorine-labeled deoxyglucose
  • PET positron emission tomography
  • standard solutions of FDG may be used in conducting standard procedures of conducting PET imaging of a tumor.
  • the uptake of FDG in cells of the highly glycolytic tumor is at least 2-3 times that of the uptake of FDG in normal cells, or at least 3-4 times that of the uptake of FDG in normal cells, or at least 4-5 times that of the uptake of FDG in normal cells, or at least 5-6 times that of the uptake of FDG in normal cells, or at least 6-7 times that of the uptake of FDG in normal cells.
  • the cancer is associated with tissue of the bladder, bone marrow, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, skin or thyroid.
  • the method of treating cancer further comprises conjointly administering radiation therapy.
  • the invention provides for the use of a compound of the invention in combination with radiation therapy.
  • An optimized dose of radiation therapy may be given to a subject as a daily dose.
  • Optimized daily doses of radiation therapy may be from 0.25 to 0.5 Gy, 0.5 to 1.0 Gy, 1.0 to 1.5 Gy, 1.5 to 2.0 Gy, 2.0 to 2.5 Gy, and 2.5 to 3.0 Gy.
  • the daily dose of radiation is from 2.0 to 3.0 Gy.
  • a higher dose of radiation may be administered if a tumor is resistant to lower doses of radiation.
  • High doses of radiation may reach 4 Gy.
  • the total dose of radiation administered over the course of treatment may range from 50 to 200 Gy. In some embodiments, the total dose of radiation administered over the course of treatment ranges from 50 to 80 Gy.
  • a dose of radiation is given over a time interval of 1, 2, 3, 4, or 5 minutes, wherein the amount of time is dependent on the dose rate of the radiation source.
  • a daily dose of optimized radiation may be administered 4 or 5 days a week, for approximately 4 to 8 weeks.
  • a daily dose of optimized radiation may be administered daily seven days a week, for approximately 4 to 8 weeks.
  • a daily dose of radiation may be given a single dose.
  • a daily dose of radiation may given as two or more doses.
  • the optimized dose of radiation may be a higher dose of radiation than can be tolerated by the subject on a daily base. As such, high doses of radiation may be administered to a subject, but in less frequent dosing regimen.
  • the invention is not limited to any particular type of radiation.
  • the types of radiation that may be used in cancer treatment are well known in the art and include electron beams, high-energy photons from a linear accelerator or from radioactive sources such as cobalt or cesium, protons, and neutrons.
  • ionizing radiation may be x- ray radiation.
  • the invention is not limited to any particular method of administering the radiation.
  • Methods to administer radiation are well known in the art. Such methods include, but are not limited to, external beam radiation, internal beam radiation, and radiopharmaceuticals.
  • external beam radiation a linear accelerator is used to deliver high-energy x-rays to the area of the body affected by cancer. Because the source of radiation originates from outside of the body, external beam radiation may be used to treat large areas of the body with a uniform dose of radiation.
  • Internal radiation therapy also known as brachytherapy, involves delivery of a high dose of radiation to a specific site in the body.
  • Radioactive material may also be delivered to tumor cells by attachment to tumor- specific antibodies.
  • the radioactive material used in internal radiation therapy is typically contained in a small capsule, pellet, wire, tube, or implant.
  • radiopharmaceuticals are unsealed sources of radiation that may be given orally, intravenously or directly into a body cavity.
  • Radiation therapy may also include stereotactic surgery or stereotactic radiation therapy, wherein a precise amount of radiation is delivered to a small tumor area using a linear accelerator or gamma knife and three-dimensional conformal radiation therapy (3DCRT), which is a computer assisted therapy to map the location of the tumor prior to radiation treatment.
  • 3DCRT three-dimensional conformal radiation therapy
  • the method of treating cancer further comprises conjointly administering one or more additional chemotherapeutic agents.
  • Chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, Bacillus Calmette–Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxor
  • chemotherapeutic agents that may be conjointly administered with compounds of the invention include: aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil,
  • the chemotherapeutic agent conjointly administered with compounds of the invention is a taxane chemotherapeutic agent, such as paclitaxel or docetaxel.
  • the chemotherapeutic agent conjointly administered with compounds of the invention is doxorubicin.
  • a compound of the invention is administered conjointly with a taxane
  • chemotherapeutic agent e.g., paclitaxel
  • doxorubicin doxorubicin
  • the chemotherapeutic agent is selected from
  • diethylstilbestrol docetaxel, doxorubicin, epirubicin, eribulin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomaide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine,
  • medroxyprogesterone megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, mutamycin, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblast
  • the methods include conjoint administration with a chemotherapeutic agent selected from afatinib dimaleate, bevacizumab, carboplatin, ceritinib, cisplatin, crizotinib, docetaxel, doxorubicin hydrochloride; erlotinib
  • a chemotherapeutic agent selected from afatinib dimaleate, bevacizumab, carboplatin, ceritinib, cisplatin, crizotinib, docetaxel, doxorubicin hydrochloride; erlotinib
  • hydrochloride etoposide, gefitinib, gemcitabine hydrochloride, mechlorethamine hydrochloride, methotrexate, paclitaxel, pemetrexed disodium, ramucirumab, topotecan hydrochloride, and vinorelbine tartrate.
  • combination therapies have been developed for the treatment of cancer.
  • compounds of the invention may be conjointly administered with a combination therapy.
  • Examples of combination therapies with which compounds of the invention may be conjointly administered are included in Table 1.
  • Table 1 Exemplary combinatorial therapies for the treatment of cancer.
  • inhibitors of metabolic enzymes such as inhibitors of glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and/or glutaminase.
  • the conjointly administered chemotherapeutic agent is an immuno-oncology therapeutic, such as an inhibitor of arginase, CTLA-4, indoleamine 2,3- dioxygenase, and/or PD-1/PD-L1.
  • the immuno- oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab,
  • the invention provides for the use of a compound of the invention in combination with an AMPK agonist for simultaneous, subsequent, or sequential administration.
  • AMPK agonists include, but are not limited to, the following: biguanides (e.g., metformin, phenformin, buformin, or proguanil); resveratrol; AICA- riboside (5-aminoimidazole-4-carboxamide riboside); AICA base (5-aminoimidazole-4- carboxamide); SAICAR (5-amino-4-imidazole-N-succinocarboxamide riboside); ZMP (5- aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl-5’-monophosphate); 6-MPR (6- mercaptopurine riboside); or a pharmaceutically acceptable salt of any of the foregoing.
  • biguanides e.g., metformin, phenformin, buformin, or proguanil
  • the invention provides for the use of a compound of the invention in combination with another antitumor agent for simultaneous, subsequent, or sequential administration.
  • Said“antitumor agents” include, but are not limited to, the following: platinum-based agents, such as carboplatin and cisplatin; nitrogen mustard alkylating agents; nitrosourea alkylating agents, such as carmustine (BCNU) and other alkylating agents; antimetabolites, such as methotrexate; purine analog antimetabolites; pyrimidine analog antimetabolites, such as fluorouracil (5-FU), gemcitabine, and capecitabine; hormonal antineoplastics, such as goserelin, leuprolide, and tamoxifen;
  • natural antineoplastics such as taxanes (e.g., docetaxel and paclitaxel), aldesleukin, interleukin-2, etoposide (VP-16), interferon alfa, and tretinoin (ATRA); antibiotic natural antineoplastics, such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin; and vinca alkaloid natural antineoplastics, such as vinblastine and vincristine.
  • taxanes e.g., docetaxel and paclitaxel
  • aldesleukin e.g., interleukin-2, etoposide (VP-16), interferon alfa, and tretinoin (ATRA)
  • antibiotic natural antineoplastics such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin
  • vinca alkaloid natural antineoplastics such as vin
  • the invention provides for the use of a compound of the invention in combination with another agent for simultaneous, subsequent, or sequential administration, where the other agent need not be considered as an antitumor agent.
  • agents include the following: dactinomycin; daunorubicin HCl; docetaxel;
  • doxorubicin HCl epoetin alfa; etoposide (VP-16); ganciclovir sodium; gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine HCl; methadone HCl; ranitidine HCl;
  • fluorouracil may be formulated with epinephrine and bovine collagen to form a combination, which may be used along with a compound of any one of embodiments 1 to 215.
  • the invention provides for the use of a compound of the invention in combination with an additional chemotherapeutic agent for simultaneous, subsequent, or sequential administration.
  • additional chemotherapeutic agents include, but are not limited to, the following: altretamine, asparaginase, BCG, bleomycin sulfate, busulfan, carboplatin, carmustine (bis-chloroethylnitrosourea), chlorambucil, cisplatin, claladribine, 2-chloro-deoxyadenosine, cyclophosphamide, cytarabine, dacarbazine imidazole carboxamide, dactinomycin, daunorubicin-daunomycin, dexamethasone, doxorubicin, etoposide, floxuridine, fluorouracil, fluoxymesterone, flutamide, fludarabine, goserelin, hydroxyurea, idarubicin H
  • the invention provides for the use of a compound of the invention in combination with an autophagy inhibitor agent for simultaneous, subsequent, or sequential administration.
  • autophagy inhibitor agents include, but are not limited to, chloroquine, hydroxychloroquine, and Spautin-1.
  • the invention provides for the use of a compound of the invention in combination with another active substance for simultaneous, subsequent, or sequential administration.
  • Such other biological substances include, but are not limited to, the following: other chemotherapeutic agents, scavenger compounds, antibiotics, antivirals, anti-fungals, anti-inflammatories, vasoconstrictors and anticoagulants, and antigens useful for cancer vaccine applications.
  • Scavenger compounds include, but are not limited to the following: thiol-containing compounds such as glutathione, thiourea, and cysteine; alcohols such as mannitol, substituted phenols; quinones, substituted phenols, aryl amines; and nitro compounds.
  • conjoint administration of the hexokinase II inhibitor(s) of Formula (I) or (Ia) with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the hexokinase II inhibitor (e.g., a compound of Formula I or (Ia)) or the one or more additional therapeutic agent(s).
  • the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the hexokinase II inhibitor and the one or more additional therapeutic agent(s).
  • coadministration produces a synergistic effect.
  • the hexokinase II inhibitor and the one or more additional chemotherapeutic agents are administered simultaneously.
  • the one or more additional chemotherapeutic agents are administered within about 5 minutes to within about 168 hours prior to or after administration of the hexokinase II inhibitor.
  • the invention may provide for the use of a compound of any one of embodiments 1 to 215 for the treatment of a parasitic infection that relies heavily on glycolysis for the generation of ATP.
  • a parasitic infection may include Trypanosoma brucei and Trypanosoma cruzi.
  • Other such parasites may include Plasmodium falciparum and Brugia malayi.
  • the invention may provide for the use of a compound of Formula (I) or (Ia) to induce tumor-specific oxidative stress cell death.
  • the method comprises increasing the production of reactive oxygen species (such as free radical compounds) in tumor cells relative to normal cells.
  • the method comprises inhibition of glycolysis and NADPH synthesis, whereby the level of ROS is increase in a tumor cell relative to a normal cell.
  • the invention provides methods of inhibiting proliferation of a cancerous cell comprising contacting a cancerous cell with an effective amount of a compound of Formula (I) or (Ia).
  • the invention also provides methods of inhibiting hexokinase activity in a cell, comprising contacting a cell with a compound of of Formula (I) or (Ia).
  • the cell is a cancer cell. Such methods may be performed in vivo or in vitro. III. KITS
  • the present invention provides a kit comprising: a) one or more single dosage forms of a hexokinase inhibitor described herein; b) one or more single dosage forms of a chemotherapeutic agent as mentioned above; and c) instructions for the administration of the compound of the invention and the chemotherapeutic agent for the treatment of cancer.
  • the present invention provides a kit comprising:
  • a pharmaceutical formulation e.g., one or more single dosage forms
  • a pharmaceutical formulation comprising a compound of the invention
  • the kit further comprises instructions for the administration of the pharmaceutical formulation comprising a compound of the invention conjointly with a chemotherapeutic agent as mentioned above.
  • the kit further comprises a second pharmaceutical formulation (e.g., as one or more single dosage forms) comprising a chemotherapeutic agent as mentioned above.
  • kits for detecting whether a subject having a cancer is likely to be responsive to hexokinase inhibitors may include one or more agents for detecting the amount of expression of a protein of the invention [e.g., the amount of the protein, and/or the amount of a nucleic acid (e.g., an mRNA) encoding the protein].
  • the agents in the kit can encompass, for example, antibodies specific for the proteins, or probes specific for the mRNA that can be used to hybridize to the RNA (or to a cDNA generated from it) or to perform RT-PCR.
  • the kit may also include additional agents suitable for detecting, measuring and/or quantitating the amount of protein or nucleic acid.
  • kits of the invention can be used in experimental applications. A skilled worker will recognize components of kits suitable for carrying out a method of the invention.
  • kits of the invention may comprise instructions for performing the method.
  • Optional elements of a kit of the invention include suitable buffers, containers, or packaging materials.
  • the reagents of the kit may be in containers in which the reagents are stable, e.g., in lyophilized form or stabilized liquids.
  • the reagents may also be in single use form, e.g., for the performance of an assay for a single subject. IV. PHARMACEUTICAL COMPOSITIONS
  • the present invention provides pharmaceutical
  • compositions comprising a compound of any preceding claim and a pharmaceutically acceptable carrier.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
  • oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil
  • glycols such as propylene glycol
  • polyols such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • (13) agar (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide
  • alginic acid (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) modified and unmodified cyclodextrins, and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • compositions or compositions include bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the amount of a compound of the invention in the unit dosage form ranges from 50 to 1000 mg, or from 100 to 500 mg. In some embodiments, the amount of compound in the unit dosage form is 100 mg, or 150 mg, or 200 mg, or 250 mg, or 300 mg, or 350 mg, or 400 mg, or 450 mg, or 500 mg.
  • the amount of drug administered at any single administration ranges from 100 mg/m 2 to 2000 mg/m 2 , or from 250 mg/m 2 to 1500 mg/m 2 , or from 500 mg/m 2 to 1500 mg/m 2 , where the m 2 unit refers to the body surface area of the subject.
  • the amount of drug administered at any single administration is 500 mg/m 2 , or 750 mg/m 2 , or 1000 mg/m 2 , or 1250 mg/m 2 , or 1500 mg/m 2 .
  • a compound of the invention may be administered one or more times a day, such as once a day, twice a day, or three times a day.
  • Such dosing may occur for a set period of time or a series of set periods of time.
  • a compound of the invention may be administered to a subject one or more times a day for a period of 1-4 weeks, such as one week, two weeks, or three weeks, or four weeks.
  • a period may be followed by a rest period of 1-4 weeks (or one week, two weeks, three weeks, or four weeks), which may then be followed by another administration period of 1-4 weeks (or one week, two weeks, three weeks, or four weeks).
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents,
  • pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • compositions may also comprise buffering agents.
  • Solid 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 sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,
  • disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the
  • compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, 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, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
  • compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, 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 an active compound, 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 and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No.6,583,124, the contents of which are incorporated herein by reference.
  • liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids.
  • a preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,
  • transtracheal subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • the concentration of a compound of of the invention in a liquid pharmaceutical composition ranges from 1 to 100 mg/mL, or from 5 to 70 mg/mL, or from 10 to 50 mg/mL.
  • the intravenous delivery or intra-arterial delivery of the liquid pharmaceutical composition comprising an a compound of the invention comprises continuous intravenous infusion or intra-arterial infusion of the liquid pharmaceutical composition for a time period of from 15 minutes to 3 hours, or from 15 minutes to 2 hours, or from 15 minutes to 1 hour.
  • the dose of a compound of the invention delivered to the subject can, in some embodiments, range from 50 mg/m 2 to 2000 mg/m 2 , or from 75 mg/m 2 to 1500 mg/m 2 , or from 100 mg/m 2 to 1000 mg/m 2 , where the m 2 unit refers to the surface area of the subject to whom the drug is administered.
  • a treatment regimen may involve a series of such periods of intravenous infusion or intra-arterial infusion.
  • such periods of intravenous infusion or intra-arterial infusion may occur about a week apart from each other, and may, in some embodiments, occur within a cycle that includes weeks where no infusion of the drug occurs.
  • the treatment may involve a 21-day cycle, where periods of continuous intravenous infusion or intra-arterial infusion occur on Day 1 and Day 8, or, alternatively, the treatment may involve a 28-day cycle, where periods of continuous intravenous infusion or intra-arterial infusion occur on Day 1, Day 8, and Day 15.
  • Doses of a compound of the invention may be adjusted up or down to account for various factors, such as patient health, side effects, effectiveness of the course of treatment, etc.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious
  • biopharmaceuticals A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds).
  • the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially.
  • the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
  • conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., compound of formula I) or the one or more additional therapeutic agent(s).
  • the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).
  • compositions and methods of the present invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention.
  • pharmaceutically acceptable salt includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids.
  • compositions can include forms wherein the ratio of molecules comprising the salt is not 1:1.
  • the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula (I) or (Ia).
  • the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula (I) or (Ia) per molecule of tartaric acid.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine,
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Additional Uses
  • the invention may provide methods of inhibiting proliferation of a cancerous cell comprising contacting the cancerous cell with a compound of the invention.
  • “inhibiting proliferation” refers to slowing the rate of cell division of one or more cells, which includes causing the cell death of one or more cells.
  • the cancerous cell is a cancerous cell of a highly glycolytic phenotype, as described above.
  • the contacting can occur in vitro (e.g., on a cancerous cell that has been biopsied from a tumor, or purchased from commercial sources, etc.) or in vivo (e.g., within a subject, whether the tumor has grown within the subject or has been grafted in). In some embodiments, the contacting occurs in an in vitro environment. In some other
  • the contacting occurs in an in vivo environment.
  • the invention may provide methods of suppressing anaerobic glucose metabolism in a cancerous cell.
  • the method includes administering a compound of the invention to a subject.
  • the method includes contacting the cancerous cell with a compound of the invention.
  • the invention may provide a method of inhibiting the activity of the HK2 enzyme in a cancerous cell.
  • the method includes administering a compound of the invention to a subject.
  • the method includes contacting the cancerous cell with a compound of the invention.
  • the invention may provide methods of interrupting the glycolytic pathway in a cancerous cell.
  • the method includes administering a compound of the invention to a subject.
  • the method includes contacting the cancerous cell with a compound of the invention.
  • the present invention may also provide methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
  • Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
  • a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity, age- related macular degeneration, neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
  • RA rheumatoid arthritis
  • compounds of the present invention may be utilized to treat and/or delay onset of any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc.
  • endothelial cell proliferation or other types involved in angiogenesis as well as causing cell death or apoptosis of such cell types.
  • a compound of the invention may be administered to a subject as part of a pharmaceutically composition, as described above.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino refers to an amino group substituted with an acyl group and may be represented, for example, by the formula
  • acyloxy refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
  • alkoxy refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto.
  • Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkenyl refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and “substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.
  • substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive.
  • substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • An“alkyl” group or“alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.
  • alkyl (or “lower alkyl) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a halogen
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
  • An“alkylene” group is a straight chained or branched non-aromatic hydrocarbon diradical which is completely saturated. Typically, a straight chained or branched alkylene group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkylene groups include methylene, ethylene, 1,3-n-propylene, 1,1-iso-propylene, 2,2-n-butylene, and the like. A C 1 -C 6 straight chained or branched alkylene group is also referred to as a "lower alkylene" group.
  • alkylene (or “lower alkylene) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkylenes” and “substituted alkylenes”, the latter of which refers to alkylene moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • a halogen
  • the substituents of a substituted alkylene may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Exemplary substituted alkylenes are described below.
  • C x-y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkylene, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Cx-yalkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • the terms“C2-yalkenyl” and“C2- y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds.
  • substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive.
  • substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
  • amide refers to a group
  • each R 10 independently represent a hydrogen or hydrocarbyl group, or two R 10 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and“amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by
  • each R 10 independently represents a hydrogen or a hydrocarbyl group, or two R 10 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • the term“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • R 9 and R 10 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R 9 and R 10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • carbocycle refers to a saturated or unsaturated ring in which each atom of the ring is carbon.
  • carbocycle includes both aromatic carbocycles and non-aromatic carbocycles.
  • Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.
  • Carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • the term“fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.
  • Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5- cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane.
  • Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and
  • bicyclo[4.1.0]hept-3-ene.“Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom.
  • A“cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.
  • Cycloalkyl includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined.
  • the second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • Bicyclic cycloalkyl groups may include fused bicyclic cycloalkyl groups in which each of the rings shares two adjacent atoms with the other ring. The second ring of such a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • An exemplary fused bicyclic cycloalkyl group is tetralinyl.
  • A“cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
  • carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO 2 -R 10 , wherein R 10 represents a hydrocarbyl group.
  • ester refers to a group -C(O)OR 10 wherein R 10 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.
  • ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle.
  • Ethers include“alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • halo and“halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and“heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroalkyl refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
  • heteroaryl and“hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and“heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. Heterocyclyl groups can also be substituted by oxo groups.
  • “heterocyclyl” encompasses both pyrrolidine and pyrrolidinone.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer.
  • substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • the term“oxo” refers to a carbonyl group.
  • an oxo substituent occurs on an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl)
  • the substituted group is still intended to be a saturated group.
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are“fused rings”.
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sil refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that“substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • sulfate is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae
  • R 9 and R 10 independently represents hydrogen or hydrocarbyl, such as alkyl, or R 9 and R 10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • sulfoxide is art-recognized and refers to the group -S(O)-R 10 , wherein R 10 represents a hydrocarbyl.
  • sulfonate is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
  • sulfone is art-recognized and refers to the group -S(O)2-R 10 , wherein R 10 represents a hydrocarbyl.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 10 or -SC(O)R 10 wherein R 10 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • R 9 and R 10 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R 9 taken together with R 10 and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • Protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY.
  • nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers,
  • tetrahydropyranyl ethers examples include trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • TMS trialkylsilyl ethers
  • glycol ethers such as ethylene glycol and propylene glycol derivatives and allyl ethers.
  • a therapeutic that“prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • prophylactic and/or therapeutic treatments includes prophylactic and/or therapeutic treatments.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of formula I).
  • a common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids
  • some or all of the compounds of formula (I) or (Ia) in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.
  • LC-MS data are obtained using gradient elution on a parallel MUX system, running four Waters 1525 binary HPLC pumps, equipped with a MUX-UV 2488 multichannel UV- Vis detector (recording at 215 and 254 nM) and a Leap Technologies HTS PAL
  • DIPEA diisopropylethylamine
  • HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N- methylmethanaminium hexafluorophosphate N-oxide
  • HMDS hexamethyldisilazane
  • NMP N-methylpyrrolidinone
  • SiO 2 silica gel
  • Step 1 An indole derivative (20 mmol) is dissolved in DCM (15 mL) and pyridine (40 mmol) was added. The solution is cooled to ⁇ 0 ⁇ C, and a solution of trichloroacetyl chloride (20 mmol) in DCM (5 mL) is added over the course of about 30 min. The cooling bath is removed and the reaction mixture is stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture is then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product is filtered off, dried and used without further purification. Alternatively, the reaction mixture is partitioned between water and ethyl acetate.
  • Step 1 To a suspension of D-mannose (250 g, 555 mmol) in benzyl alcohol (1.0 L) was added acetyl chloride (40 mL). The mixture was stirred at 50 o C for 2 h. Benzyl alcohol was removed under high vacuum at 75 o C. The residue was then triturated with ethyl acetate to form a white solid. It was filtered and washed with ethyl acetate to give (2S,3S,4S,5S,6R)- 2-benzyloxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol
  • Step 2 To a solution of (2S,3S,4S,5S,6R)-2-benzyloxy-6-(hydroxymethyl)tetrahydropyran- 3,4,5-triol (107.2 g, 397 mmol) in dry DMF (400 mL) was added PTSA (7.6 g, 39.7 mmol) and benzaldehyde dimethylacetal (59.5 mL, 397 mmol). The reaction mixture was stirred for 2 h at 60 o C under reduced pressure (200 mbar) using a rotary evaporator. The solvent was then evaporated, and the residue dissolved in ethyl acetate.
  • Step 3 To a suspension of (4aR,6S,7S,8R,8aS)-6-benzyloxy-2-phenyl-4,4a,6,7,8,8a- hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (114.3 g, 319 mmol) in dry toluene (1000 mL) was added Bu 2 SnO (81 g, 325 mmol). The reaction mixture was stirred for 3 h at 120 o C. It was then allowed to cool to ambient temperature.
  • Step 4 To a solution of oxalyl choride (50.3 mL, 594 mmol) in dry DCM (1000 mL) at -78 o C was slowly added DMSO (82 mL, 1.15 mol). The reaction was allow to stir 10 min, and a solution of (4aR,6S,7S,8R,8aS)-6-benzyloxy-8-methyl-2-phenyl-4,4a,6,7,8,8a- hexahydropyrano[3,2-d][1,3]dioxin-7-ol (115 g, 256 mmol) in dry DCM (500 mL) was added at -78 o C.
  • Step 1 To a solution of D-mannose (54 g, 300 mmol) in a 1L round-bottom flask was added Bu 2 SnO (7.5 g, 30 mmol), TBAB (29.1 g, 90 mmol), DIEA (131 mL, 750 mmol) and BnBr (125 mL, 1050 mmol). The reaction was stirred at 70oC for 2.5h.
  • Step 2 To a solution of above (2R,3S,4S,5R,6R)-2,4-dibenzyloxy-6- (hydroxymethyl)tetrahydropyran-3,5-diol (58 g, 161 mmol) in DMF (600 mL) in a 1L round-bottom flask was added benzaldehyde dimethyl acetal (58 mL) and p-TSA monohydrate (2 g). The reaction mixture was stirred at 50 o C overnight. After cooling to rt, the reaction was poured into ice and sodium bicarbonate. The mixture was stirred and white solid crashed out.
  • Step 3 To a solution of (4aR,6R,7S,8R,8aR)-6,8-dibenzyloxy-2-phenyl-4,4a,6,7,8,8a- hexahydropyrano[3,2-d][1,3]dioxin-7-ol (37 g) in DMSO (150 mL) in a 1L round-bottom flask was added Ac2O (250 mL). The reaction was stirred under nitrogen at 50 o C overnight. After cooling to rt, the reaction was poured into ice and sodium bicarbonate. The mixture was stirred and white solid crashed out.
  • Step 1 To a solution of (4aR,6R,8S,8aR)-6,8-dibenzyloxy-2-phenyl-4,4a,8,8a- tetrahydropyrano[3,2-d][1,3]dioxin-7-one (Intermediate 3, 0.45g, 1 mmol) in anhydrous THF (5 ml) was added anhydrous chloroform (0.4 mL, 3eq). The mixture was stirred under nitrogen at -78 o C. A 1 M solution of LiHMDS (lithium hexamethyldisilazide) in THF (3 mL) was added dropwise.
  • LiHMDS lithium hexamethyldisilazide
  • Step 2 To a solution of (4aR,6R,7S,8S,8aR)-6,8-dibenzyloxy-2-phenyl-7- (trichloromethyl)-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-ol (0.52 g, 0.92 mmol) in anhydrous methanol (5 mL) was added sodium azide (0.5 g) and 18-crown-6 (10 mg). The mixture was stirred under nitrogen at rt for 10 min.. A solution of DBU (0.67 ml, 5 eq) in THF (3 ml) was added dropwise. The reaction was stirred at 50 o C for 1h.
  • Step 3 To a suspension of LiAlH4 (40mg) in anhydrous diethyl ether was added a solution of methyl (4aR,6R,7R,8R,8aS)-7-azido-6,8-dibenzyloxy-2-phenyl-4a,6,8,8a-tetrahydro- 4H-pyrano[3,2-d][1,3]dioxine-7-carboxylate (0.1g) in anhydrous diethyl ether (2 mL) dropwise at 0 o C. The reaction was stirred at 0 o C for 30 min then further stirred at rt for 30 min.
  • reaction was quenched with a saturated aqueous solution of Na2SO4 (1ml) and was followed by addition of a 10% aqueous solution of NaOH (1 mL).
  • the mixture was extracted with DCM (2x50 mL). The organic layer was dried over MgSO 4 and condensed.
  • Step 4 [(4aR,6R,7R,8R,8aS)-7-Amino-6,8-dibenzyloxy-2-phenyl-4a,6,8,8a-tetrahydro- 4H-pyrano[3,2-d][1,3]dioxin-7-yl]methanol (0.18g) was placed in a 250-mL hydrogenation bottle and dissolved by addition of methanol (10 mL), THF (10 mL) and a solution of 4M HCl in 1,4-dioxane (0.2 mL). Pd-C (10% wet, 0.15 g) was added, the bottle was flushed several times with hydrogen.
  • Step 1 To a stirred solution of Intermediate 2 (45 g, 100.9 mmol) in THF (1 L) was added Ti(OEt)4 ( 27.6 g, 121.08 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (17.12 g, 141.26 mmol). The solution was stirred for 14 h at 50 o C, allowed to cool to room temperature and diluted with H 2 O. The resulting suspension was filtered through Celite with an EtOAc rinse and the filtrate was extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated.
  • Step 2 To a stirred solution of N-[(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7-methyl-2- phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]-2-methyl-propane-2- sulfinamide (40 g, 70.8 mmol) in dioxane (400 mL) was added HCl (37 mL, 4M dioxane solution). After 30 min. the solution was concentrated and diluted with Et 2 O. The resulting precipitate was collected by filtration, washed (10% Et2O in Hexanes) and allowed to dry.
  • Step 3 To a stirred solution of tert-butyl N-[(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7- methyl-2-phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]carbamate (14 g, 25 mmol) in THF/MeOH (260 mL, 1:1) was added palladium on carbon (5.2 g, 10% (dry basis), wet Degussa type) and HCl (15 mL, 4M dioxane solution).
  • Step 1 To a suspension of 4-fluoro-3-methoxy-aniline (37.5 g, 266 mmol) in dry DCM (500 mL) was added K 2 CO 3 (38.6 g, 279 mmol). The reaction mixture was cooled to -15 ⁇ C, and a solution of bromine (13.63 mL, 266 mmol) in DCM (100 mL) was slowly added. It was stirred at -15 ⁇ C for 1 h. The mixture was then allowed to warm to rt, and water was added. The reaction workup mixture was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo. The solid was dissolved in DCM and hexanes was added.
  • Step 2 2-Bromo-4-fluoro-5-methoxy-aniline (107 g, 0.486 mol) was dissolved in MeOH (400 mL) and methyl propiolate (130 mL, 1.46 mol) was added. The reaction mixture was stirred at reflux for 72 h. All the volatiles are removed under reduced pressure.
  • Step 3 To a solution of methyl 3-(2-bromo-4-fluoro-5-methoxy-anilino)prop-2-enoate (121.4 g, 0.399 mol) in anhydrous DMF (375 mL) was added tributylamine (190 mL, 0.799 mol) and tri(o-tolyl)phosphine (60.7 g, 0.20 mol). The reaction mixture was degassed twice then back filled with nitrogen.
  • Step 4 To methyl 5-fluoro-6-methoxy-1H-indole-3-carboxylate (38.3 g, 171.6 mmol) in dry DMF (80 mL) was added K2CO3 (35.6 g, 257.4 mmol). To this mixture was added 2- (bromomethyl)naphthalene (45.5 g, 205.9 mmol), and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. This material was dissolved in DCM/MeOH, and hexanes was added.
  • 6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid was synthesized from 6- bromoindole and 2-bromomethylnaphtlalene following General Procedure A.
  • 6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid was taken into methanol. To this solution was added 2 M trimethylsilyldiazomethane in hexane (excess, 1.2-1.5 equiv). The mixture was stirred for 30 min and was concentrated to dryness. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 6-bromo-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester.
  • This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[5,6-difluoro-1-(2-naphthylmethyl)indol-3-yl]ethanone.
  • 6-Chloro-5-fluoro-1H-indole (1.29 g, 7.4 mmol) was dissolved in DCM (20 mL) and pyridine (1.8 mL, 22.2 mmol) was added. The solution was cooled to ⁇ 0 ⁇ C, and a solution of trichloroacetyl chloride (1.24 mL, 11.1 mmol) in DCM (3 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried.
  • 6-Ethoxy-1H-indole (2.34 g, 14.5 mmol) was dissolved in DCM (15 mL) and pyridine (3.52 mL, 43.55 mmol) was added. The solution was cooled to ⁇ 0 ⁇ C, and a solution of trichloroacetyl chloride (1.28 mL, 11.4 mmol) in DCM (10 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried.
  • Methyl 2-[(4aR,6R,8R,8aS)-6,8-dibenzyloxy-2-phenyl-4,4a,8,8a-tetrahydropyrano[3,2- d][1,3]dioxin-7-ylidene]acetate was taken up in 7 N NH3/MeOH and heated in a sealed tube at 70 °C for 72 h.
  • HMDS (0.65 mL, 3.12 mmol) and TMSCl (0.396 mL, 3.12 mmol) were added to a solution of (3R,4R,5S,6R)-3-amino-3-(2-hydroxyethyl)-6-(hydroxymethyl)tetrahydropyran-2,4,5- triol hydrochloride (135 mg, 0.52 mmol) in pyridine (4 mL).
  • pyridine 4 mL
  • the reaction mixture was heated overnight at 100 °C. The mixture was allowed to cool, poured into water, and was extracted with hexanes. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed to give the crude product (200 mg).
  • HK2 Hexokinase 2
  • Human hexokinase assay utilized ATP and glucose as substrates and detection of ADP product using the ADP-Glo detection system (Promega). Assays were performed in black 384-well flat-bottom plates (Greiner). Recombinant human hexokinase 2 enzyme was purchased from US Biologicals. Compounds were diluted in DMSO prior to addition in the assay.
  • assays were performed by incubating enzyme (0.2– 10 nM) with or without inhibitor (0.00001-100 ⁇ M), 0.001-1.0 mM ATP, 0.1-100 mM MgCl2, 0.1-100 mM KCl, 1-10 mM DTT, and 0.01-10 mM glucose together for the time range of 5-120 minutes at room temperature in a final assay volume of 10 ⁇ L.
  • the buffer used to bring the final assay volume up to 10 ⁇ L was 25 mM HEPES, pH 7.4, containing 1-5% DMSO and 0.1 % BSA. Reactions were terminated by addition of 10 ⁇ L ADP-Glo and plates were incubated at room temperature for 40 minutes. Then 20 ⁇ L Kinase Detect buffer was added and plates were incubated 1 hour at room temperature with shaking. Then, the plate was read for Luminiscence using and Envision instrument (Perkin Elmer).
  • Dual Hoechst 33342 dye/ propidium iodide staining may be used to measure cell number and cell viability.
  • the antiproliferative activity of compounds may be studied using a panel of human tumor cells obtained from ATCC: SKOV-3 (human ovarian carcinoma cell line). These adherent cells (1,000– 20,000) may be plated in complete media (RPMI-1640, DMEM, F12K, or McCoy’s 5A) containing 10% dialyzed fetal bovine serum (Gibco) and glucose (1- 25 mM) in tissue-culture-treated Optilux 96-well black plates (Becton Dickinson) and placed in a humidified incubator at 37 oC, 95% O2, 5% CO2 for 18-24 hours. Media may be removed and replaced with 90 ⁇ L fresh media.
  • a compound (0.00001-100 ⁇ M) may be diluted in media containing 3% DMSO and added to cells. Untreated cells or cells containing compound may be incubated for 24-96 hours. During the last 30 minutes of the incubation period, 10 ⁇ L of a propidium iodide (10 ⁇ g/mL)/Hoescht 33342 dye reagent (32 ⁇ M) in PBS may be added to each well and incubated in a humidified incubator at 37 oC, 95% O 2 , 5% CO 2 .
  • Propidium iodide/ Hoechst 33342 fluorescent staining of cells may be measured using an IN Cell 2000 analyzer instrument with 10X objective.
  • the instrument setting for the Hoechst channel may be excitation at 350 nm and emission at 455 nm.
  • the setting for the propidium iodide channel may be excitation at 550 nm and emission at 605 nm.
  • the nuclei may be counted in the Hoechst 33342 channel; the dead cells may be counted in the propidium iodide channel.
  • Exemplary compounds of the invention were analyzed via the In Vitro Cell Proliferation Assay above. Results are shown in Table 3 below. Table 3
  • Recombinant human hexokinase 2 was purchased from R and D Systems (product #8179- HK-020) and assayed using the Universal Kinase Activity Kit from R and D Systems (product #EA004) according to the manufacturer’s instruction.
  • the assay couples to production of ADP by hexokinase to the generation of phosphate by the coupling phosphatase CD39L2/ENTPD6. Phosphate is then reacted with malachite green and the colored product is measured by absorbance at 620 nm.
  • H838 cells were obtained from the American Type Culture Collection (ATCC) and cultured in 5% CO 2 at 37 ⁇ C. Cells were seeded at 5,000 cells/well in RPMI 1640 media
  • Vehicle control 50% sulfobutyl ether- ⁇ -cyclodextrin
  • HKII inhibitor dosed at intraperitoneally at 50 mg/kg (formulated at 5 mg/mL in 40% SBECD). For both groups, dosing was initiated on Day 14 and continued twice daily intraperitoneally until study end.

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Abstract

L'invention concerne des hétérocycles substitués utiles en tant qu'inhibiteurs de l'enzyme HKII. L'invention concerne aussi des compositions pharmaceutiques des composés de l'invention. L'invention concerne en outre des utilisations médicales des hétérocycles substitués, par exemple, comme agents antitumoraux.
PCT/US2017/040715 2016-07-05 2017-07-05 Inhibiteurs d'hexokinase et leurs procédés d'utilisation WO2018009539A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée
US12116382B2 (en) 2022-11-28 2024-10-15 Hongene Biotech Corporation Functionalized N-acetylgalactosamine analogs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012083145A1 (fr) * 2010-12-17 2012-06-21 Glaxo Wellcome Manufacturing Pte Ltd Dérivés de glucosamine
WO2012123774A1 (fr) * 2011-03-11 2012-09-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteur glycolytique en combinaison à un agent cytotoxique pour l'utilisation dans le traitement d'un cancer
WO2016196890A1 (fr) * 2015-06-04 2016-12-08 Vtv Therapeutics Llc Inhibiteurs d'hexokinase et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012083145A1 (fr) * 2010-12-17 2012-06-21 Glaxo Wellcome Manufacturing Pte Ltd Dérivés de glucosamine
WO2012123774A1 (fr) * 2011-03-11 2012-09-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteur glycolytique en combinaison à un agent cytotoxique pour l'utilisation dans le traitement d'un cancer
WO2016196890A1 (fr) * 2015-06-04 2016-12-08 Vtv Therapeutics Llc Inhibiteurs d'hexokinase et leurs procédés d'utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022140246A1 (fr) 2020-12-21 2022-06-30 Hangzhou Jijing Pharmaceutical Technology Limited Procédés et composés destinés à l'autophagie ciblée
US12116382B2 (en) 2022-11-28 2024-10-15 Hongene Biotech Corporation Functionalized N-acetylgalactosamine analogs

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