WO2016196890A1 - Inhibitors of hexokinase and methods of use thereof - Google Patents

Inhibitors of hexokinase and methods of use thereof Download PDF

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Publication number
WO2016196890A1
WO2016196890A1 PCT/US2016/035663 US2016035663W WO2016196890A1 WO 2016196890 A1 WO2016196890 A1 WO 2016196890A1 US 2016035663 W US2016035663 W US 2016035663W WO 2016196890 A1 WO2016196890 A1 WO 2016196890A1
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Prior art keywords
alkyl
cycloalkyl
heterocyclyl
compound
aralkyl
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PCT/US2016/035663
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French (fr)
Inventor
Adnan M.M. Mjalli
Bapu Gaddam
Devi Reddy Gohimukkula
Dharma Rao Polisetti
Mohan Rao
Mustafa Guzel
Nidhi Singh
Rima HAJJO
Robert Carl Andrews
Rongyuan Xie
Santhosh Kalpathy
Soumya Prakash SAHOO
Stephen Thomas Davis
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Vtv Therapeutics Llc
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Publication of WO2016196890A1 publication Critical patent/WO2016196890A1/en

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    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms

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): - 1 -
  • R 1 -R 6 , R 8a , R 8b , R 9a , R 9b , Z, and X 1 are as defined in the specification.
  • the invention relates to compounds having the structure of Formula (II):
  • R 3 -R 6 , R 8a , R 8b , R 9a , R 9b , Z, and X 1 are as defined in the specification.
  • the invention relates to pharmaceutical compositions of a compound of Formula (I) or Formula (II), 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.
  • the invention provides substituted pyran derivatives or substituted fused oxazoline derivatives, and pharmaceutical compositions thereof.
  • substituted pyran derivatives and fused oxazoline derivatives are useful as HKII inhibitors, and thus can be used as antitumor agents, antifungal agents, or an anti-angiogenesis inhibitors.
  • the invention relates to compounds having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
  • R 1 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
  • heterocyclyl alkyl, aralkyl, or heteroaralkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, and heteroaralkyl groups are optionally substituted;
  • R 2 represents -OH
  • R 3 represents -OH, -O-R 31 , -NH 2 , -NH-R 31 , or NR 31 R 32 ;
  • R 4 represents -OH, -O-R 41 , -NH 2 , -NH-R 41 , or NR 41 R 42 ;
  • 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 5 represents -CR a R b -, -C(O)-, or a bond
  • Z represents O, NH, NR Z1 , or NC(O)R Z1 ;
  • X 1 represents N or C-R 7 ;
  • R 6 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(O)-R 61 , -C(O)-OR 61 , -C(O)-NR 61 , -C(S)-R 61 ,-C(S)-NR 61 , or -SO 2 -R 61 , where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
  • R 7 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R 71 , -SH, -S- R 71 , -S(O)R 71 , -SO 2 -R 71 , -NH 2 , -NH-R 71 , -NR 71 R 72 , -C(O)-R 71 , -CO 2 H, -C(O)-O- R 71 , -O-C(O)-R 71 , -O-C(O)-OR 71 , -C(O)-NH 2 , -C(O)-NH-R 71 , -C(O)-NR 71 R 72 , -NH- C(O)
  • R 8a and R 8b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
  • heterocyclylalkyl aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
  • R 9a and R 9b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
  • heterocyclylalkyl aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
  • R 61 , R 71 , R 72 , 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; or R 71 and R 72 , R 81 and R 82 , or R 91 and R 92 , 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 31 , R 32 , R 41 , R 42 , R 51 , and R 52 are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, -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 , where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and aralkyl groups are optionally substituted; and
  • R 103 and R 104 independently for each occurrence represent substituted or unsubstituted
  • alkyl cycloalkyl, (cycloalkyl)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 and R b are each independently selected from H, alkyl, (cycloalkyl)alkyl, aralkyl,
  • heteroaralkyl alkenyl, and alkynyl
  • R Z1 represents alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, haloalkyl, alkoxy, or haloalkoxy.
  • R 5 represents -G 5 -OH or - G 5 -O-R 51 .
  • R 5 represents -G 5 -NH 2 , -G 5 -NH-R 51 , or -G 5 -NR 51 R 52 .
  • G 5 represents -CR a R b -.
  • R a and R b are each independently selected from H or a carbon-based substituent such as alkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, or alkynyl.
  • G 5 can be -C(alkyl) 2 - or -CH(alkyl).
  • G 5 is -CH 2 -.
  • G 5 represents -C(O)-.
  • R 5 represents -CH 2 OH.
  • R 5 represents -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, (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, trifluoromethoxy.
  • R 51 is methyl, ethyl, or isopropyl.
  • R 5 represents -CH 2 -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 -SO 2 -R 103 .
  • R 51 is -C(O)-R 103 .
  • R 103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 5 represents -CH 2 -NH 2 .
  • 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 -CH 2 NH-R 51 or -CH 2 NR 51 R 52 .
  • R 51 and R 52 are 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 5 represents - CH 2 NH-R 51 , wherein R 51 is -C(O)-R 103 or -SO 2 -R 103 .
  • R 103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
  • R 103 represents 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.
  • isoxazolyl e.g., isoxazol-5-yl
  • phenyl e.g., imidazolyl (e.g., imidazol-4-yl)
  • oxazolyl e.g., 2-oxazolyl
  • benzyl optionally substituted at any position with one or more substituents selected from halogen, hydroxy, me
  • R 1 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl, optionally substituted at any position by one of more substituents R 15 , wherein: R 15 , independently for each occurrence, 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
  • 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 1 represents methyl, ethyl, isopropyl, propyl, or butyl. In certain preferred embodiments, R 1 represents H.
  • Z represents O or NH. In preferred embodiments, Z represents O.
  • R 3 represents -O-R 31 , wherein R 31 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, 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 31 can be 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, trifluoromethoxy.
  • R 31 is methyl, ethyl, or isopropyl.
  • 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 3 represents -OH.
  • R 3 represents -NH 2 or -NH-R 31 , wherein R 31 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 31 is methyl, ethyl, or isopropyl.
  • R 31 can be -C(O)-R 103 , -C(O)-O-R 103 , -C(O)-N(H)-R 103 , -C(O)-NR 103 R 104 , or -SO 2 -R 103 , preferably -C(O)-R 103 or -SO 2 -R 103 .
  • R 103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
  • R 4 represents -O-R 41 , wherein R 41 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, 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 41 can be 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, trifluoromethoxy.
  • R 41 is methyl, ethyl, or isopropyl.
  • 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 .
  • R 41 is -C(O)-R 103 .
  • R 103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 4 represents -OH.
  • R 4 represents -NH 2 or -NH-R 41 , wherein R 41 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 41 is methyl, ethyl, or isopropyl.
  • R 41 can be -C(O)-R 103 , -C(O)-O-R 103 , -C(O)-N(H)-R 103 , -C(O)-NR 103 R 104 , or -SO 2 -R 103 , preferably -C(O)-R 103 or -SO 2 -R 103 .
  • R 103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
  • R 3 and R 4 are both -OH.
  • X 1 represents N or CH.
  • X 1 represents N.
  • X 1 represents N, or CR 7 , wherein R 7 represents hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R 75 , wherein:
  • R 75 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)- NH 2 , -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.
  • X 1 represents N or CR 7 , wherein R 7 represents -OH, -O- R 71 , -SH, -S-R 71 , -S(O)R 71 , -SO 2 -R 71 , -NH 2 , -NH-R 71 , -NR 71 R 72 , -C(O)-R 71 , -CO 2 H, -C(O)- O-R 71 , -O-C(O)-R 71 , -O-C(O)-OR 71 , -C(O)-NH 2 , -C(O)-NH-R 71 , -C(O)-NR 71 R 72 , -NH- C(O)-R 71 , -N(R 72 )-C(O)-R 71 , -NH-C(O)-NH 2 , -NH-C(O)-NHR 71 , -
  • X 1 is CR 7 , wherein R 7 represents lower alkyl, e.g., methyl, ethyl, or isopropyl.
  • X 1 represents CH.
  • R 6 represents H. In certain embodiments, R 6 represents -C(O)-R 61 , -C(O)-OR 61 , -C(O)-NR 61 , -C(S)- R 61 ,-C(S)-NR 61 , or -SO 2 -R 61 , wherein R 61 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R 6 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R 6 represents alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R 65 , wherein:
  • R 65 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)- NH 2 , -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 6 represents substituted or unsubstituted (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl. In certain such embodiments, R 6 is substituted at any position with one or more substituents R 65 , wherein R 65 is defined above.
  • R 6 represents substituted or unsubstituted -CH 2 -(1- naphthyl), -CH 2 -(2-naphthyl), or -CH 2 -(phenyl). In certain such embodiments, R 6 is substituted at any position with one or more substituents R 65 , wherein R 65 is defined above.
  • R 65 represents halo, hydroxyl, -CO 2 H, cyano, or optionally substituted alkyl, alkoxy, haloalkyl, haloalkoxy, -SO 2 -(alkyl), -C(O)-O-(alkyl), -S(alkyl), -S(haloalkyl), heteroaryl, or aryl.
  • R 6 represents -CH 2 -(1-naphthyl), -CH 2 -(2-naphthyl), or -CH 2 -(phenyl), substituted at any position by one or more substituents R 65 , wherein each occurrence of R 65 is independently selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
  • R 6 is not hydrogen
  • 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 selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -C 3-10 cycloalkyl, where the cycloalkyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is cyclohexylmethyl.
  • R 6 is (heterocyclyl)alkyl, (e.g., -C 1-6 alkylene-heterocyclyl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -heterocyclyl, where the heterocyclyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is tetrahydropyran-4-ylmethyl.
  • R 6 is heteroaralkyl (e.g., -C 1-6 alkylene-heteroaryl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -heteroaryl, where the heteroaryl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -pyridyl, where the pyridyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain embodiments, R 6 is -CH 2 -pyridyl, where the pyridyl group is optionally substituted with one or two chloro groups.
  • R 6 is 2-chloro-pyridin-5-ylmethyl.
  • R 6 is–CH 2 -benzothiazol-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH 2 -benzofuran-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH 2 -benzothiphene-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH 2 -quinoxalin-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is–CH 2 -benzimidazol-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
  • R 6 is substituted or unsubstituted aralkyl (e.g., -C 1-6 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 selected independently from the group consisting of fluoro, chloro, methyl, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH(CH 3 )-phenyl.
  • R 6 is -CH 2 -aryl, optionally substituted by one or more occurrences of R 65 , as defined above.
  • R 6 is -CH 2 -aryl, where the aryl group is naphthyl, optionally substituted by one or more occurrences of R 65 , as defined above.
  • R 6 is -CH 2 -(2-naphthyl), -CH 2 -(1-naphthyl), or -CH(CH 3 ) 2 - naphthyl, where the naphthyl group is optionally substituted one or more times with substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -(2-naphthyl).
  • 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 -CH 2 -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, -SO 2 -CH 3 , -CO 2 CH 3 , -CO 2 H, 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 8a and R 8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR 81 , halogen, and cyano.
  • R 8a is hydrogen
  • R 8a is not hydrogen
  • R 8a is -OH or -O-R 81 .
  • 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.
  • R 8b is not hydrogen
  • R 8b is -OH or -O-R 81 .
  • 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 and R 8b are each hydrogen.
  • R 9a and R 9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR 91 , halogen, and cyano.
  • At least one of R 9a and R 9b represents -OR 91 .
  • R 91 represents alkyl.
  • 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 , -CO 2 H, -C(O)-O-R 101 , -O-C(O)-R 101 , O-C(O)-OR 101 , -C(O)- NH 2 , -C(O)-NH-R 101 , -C(O)-NR 101 R 102 , -NH-C(O)-R 101
  • R 9a is hydrogen. In other embodiments, R 9a is not hydrogen.
  • R 9a is -OH or -O-R 91 .
  • R 9a is -O-R 91 .
  • R 91 is C 1-4 alkyl, e.g., methyl.
  • R 9a is halogen, e.g., bromo or chloro.
  • R 9a is C 1-6 alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 9a is C 2-6 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)- NH 2 , -C(O)-NH-R 101 , -C(O)-NR 101 R 102 , -NH-C(O)-R 101
  • 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, C 1-6 alkyl, -O-R 91 , -CO 2 H, -CO 2 -R 91 , -S(O) 2 -R 91 , and hydroxyl, and R 91 is C 1 -C 6 alkyl C 1 -C 6 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. In certain such embodiments, R 95 is methyl.
  • R 9b is hydrogen. In other embodiments, R 9b is not hydrogen.
  • R 9b is -OH or -O-R 91 .
  • R 9b is -O-R 91 .
  • R 91 is C 1-4 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–CO 2 H.
  • 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 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 , -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)- NH 2 , -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 9b is phenyl, optionally substituted with one or more substituents R 95 , wherein each occurrence of R 95 is independently selected from chloro, fluoro, C 1-6 alkyl, -O-R 91 , -CO 2 H, -CO 2 -R 91 , -S(O) 2 -R 91 , and hydroxyl, and R 91 is C 1 -C 6 alkyl C 1 -C 6 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 .
  • R 6 , R 8a , R 8b , R 9a , and R 9b is not H.
  • the invention relates to compounds having the structure of Formula (II), or a pharmaceutically acceptable salt thereof:
  • R 3 represents -OH, -O-R 31 , -NH 2 , -NH-R 31 , or NR 31 R 32 ;
  • R 4 represents -OH, -O-R 41 , -NH 2 , -NH-R 41 , or NR 41 R 42 ;
  • 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 5 represents -CR a R b -, -C(O)-, or a bond
  • Z represents O, NH, NR Z1 , or NC(O)R Z1 ;
  • X 1 represents N or C-R 7 ;
  • R 6 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(O)-R 61 , -C(O)-OR 61 , -C(O)-NR 61 , -C(S)-R 61 , -C(S)-NR 61 , or -SO 2 -R 61 , where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
  • R 7 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R 71 , -SH, -S- R 71 , -S(O)R 71 , -SO 2 -R 71 , -NH 2 , -NH-R 71 , -NR 71 R 72 , -C(O)-R 71 , -CO 2 H, -C(O)-O- R 71 , -O-C(O)-R 71 , -O-C(O)-OR 71 , -C(O)-NH 2 , -C(O)-NH-R 71 , -C(O)-NR 71 R 72 , -NH- C(O)
  • cycloalkyl alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
  • 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 61 , R 71 , R 72 , R 81 , R 82 , R 91 , and R 92 are each independently selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl,;
  • R 71 and R 72 , R 81 and R 82 , or R 91 and R 92 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 31 , R 32 , R 41 , R 42 , R 51 , and R 52 are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, -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 , where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and aralkyl groups are optionally substituted;
  • R 103 and R 104 independently for each occurrence represent substituted or unsubstituted
  • alkyl cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or (cycloalkyl)alkyl;
  • 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 and R b are each independently selected from H, alkyl, (cycloalkyl)alkyl, aralkyl,
  • heteroaralkyl alkenyl, and alkynyl
  • R Z1 represents alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, haloalkyl, alkoxy, or haloalkoxy;
  • R 6 , R 8a , R 8b , R 9a , and R 9b is not hydrogen.
  • Z represents O or NH. In preferred embodiments, Z represents O.
  • X 1 represents N or CH. In certain embodiments, X 1 represents N.
  • X 1 represents N, or CR 7 , wherein R 7 represents hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R 75 , wherein:
  • R 75 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)- NH 2 , -C(O)-NH-R 101 , -C(O)-NR 101 R 102 , -NH-C(O)-R 101
  • X 1 represents N or CR 7 , wherein R 7 represents -OH, -O- R 71 , -SH, -S-R 71 , -S(O)R 71 , -SO 2 -R 71 , -NH 2 , -NH-R 71 , -NR 71 R 72 , -C(O)-R 71 , -CO 2 H, -C(O)- O-R 71 , -O-C(O)-R 71 , -O-C(O)-OR 71 , -C(O)-NH 2 , -C(O)-NH-R 71 , -C(O)-NR 71 R 72 , -NH- C(O)-R 71 , -N(R 72 )-C(O)-R 71 , -NH-C(O)-NH 2 , -NH-C(O)-NHR 71 , -
  • X 1 is CR 7 , wherein R 7 represents lower alkyl, e.g., methyl, ethyl, isopropyl, or butyl.
  • X 1 represents CH.
  • R 3 represents -OH or -O-R 31
  • R 4 represents -OH or -O- R 41 .
  • R 3 represents -OH or -O-R 31 , wherein R 31 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, 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 31 can be 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, trifluoromethoxy.
  • R 31 is methyl, ethyl, or isopropyl.
  • R 3 represents -OH or -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 3 represents -OH.
  • R 3 represents -NH 2 or -NH-R 31 , wherein R 31 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 31 is methyl, ethyl, or isopropyl.
  • R 31 can be -C(O)-R 103 , -C(O)-O-R 103 , -C(O)-N(H)-R 103 , -C(O)-NR 103 R 104 , or -SO 2 -R 103 , preferably -C(O)-R 103 or -SO 2 -R 103 .
  • R 103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
  • R 4 represents -OH or -O-R 41 , wherein R 41 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, 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 41 can be 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, trifluoromethoxy.
  • R 41 is methyl, ethyl, or isopropyl.
  • R 4 represents -OH or -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 .
  • R 41 is -C(O)-R 103 .
  • R 103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 4 represents -OH.
  • R 4 represents -NH 2 or -NH-R 41 , wherein R 41 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 41 is methyl, ethyl, or isopropyl.
  • R 41 can be -C(O)-R 103 , -C(O)-O-R 103 , -C(O)-N(H)-R 103 , -C(O)-NR 103 R 104 , or -SO 2 -R 103 , preferably -C(O)-R 103 or -SO 2 -R 103 .
  • R 103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
  • R 3 represents -O-R 31 and R 4 represents -O-R 41 , wherein R 31 and R 41 are each independently selected from alkyl, -C(O)-R 103 , and -SO 2 -R 103 , wherein R 103 is as described above.
  • R 3 and R 4 are both -OH.
  • R 5 represents -G 5 -OH or - G 5 -O-R 51 .
  • R 5 represents -G 5 -OH.
  • R 5 represents -G 5 -NH 2 , -G 5 -NH-R 51 , or -G 5 -NR 51 R 52 . In certain embodiments, R 5 represents -G 5 -NH 2 or -G 5 -NH-R 51 .
  • R 5 represents -G 5 -NH 2 .
  • G 5 represents -CR a R b -.
  • R a and R b are each independently selected from H or a carbon-based substituent such as alkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, or alkynyl.
  • G 5 can be -C(alkyl) 2 - or -CH(alkyl).
  • G 5 is -CH 2 -.
  • R 5 represents -CH 2 OH.
  • R 5 represents -G 5 -O-R 51 , e.g., -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, (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, trifluoromethoxy.
  • R 51 is methyl, ethyl, or isopropyl.
  • R 5 represents -G 5 -O-R 51 , e.g., -CH 2 -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 -SO 2 - R 103 .
  • R 51 is -C(O)-R 103 .
  • R 103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 5 represents -G 5 -O-R 51
  • R 51 represents alkyl, -C(O)- R 103 , and -SO 2 -R 103 .
  • R 5 represents -CH 2 -NH 2 .
  • 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 -CH 2 NH-R 51 or -CH 2 NR 51 R 52 .
  • R 51 and R 52 are 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 5 represents - CH 2 NH-R 51 , wherein R 51 is -C(O)-R 103 or -SO 2 -R 103 .
  • R 5 represents -G 5 -NH-R 51
  • R 51 represents alkyl, -C(O)-R 103 , and -SO 2 -R 103 .
  • R 103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
  • R 103 represents 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., 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.
  • isoxazolyl e.g., isoxazol-5-yl
  • phenyl e.g., imidazolyl (e.g., imidazol-4-yl)
  • oxazolyl e.g., oxazolyl
  • benzyl optionally substituted at any position with one or more substituents selected from halogen, hydroxy, me
  • G 5 represents -C(O)-.
  • R 6 represents H.
  • R 6 represents -C(O)-R 61 , -C(O)-OR 61 , -C(O)-NR 61 , -C(S)- R 61 ,-C(S)-NR 61 , or -SO 2 -R 61 , wherein R 61 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
  • R 6 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R 6 represents alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R 65 , wherein:
  • R 65 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)- NH 2 , -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 6 represents substituted or unsubstituted (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl. In certain such embodiments, R 6 is substituted at any position with one or more substituents R 65 , wherein R 65 is defined above.
  • R 65 represents halo, hydroxyl, -CO 2 H, cyano, or optionally substituted alkyl, alkoxy, haloalkyl, haloalkoxy, -SO 2 -(alkyl), -C(O)-O-(alkyl), -S(alkyl), -S(haloalkyl), heteroaryl, or aryl.
  • each occurrence of R 65 is independently selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
  • R 6 is not hydrogen
  • 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 selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -C 3-10 cycloalkyl, where the cycloalkyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is cyclohexylmethyl.
  • R 6 is (heterocyclyl)alkyl (e.g., -C 1-6 alkylene-heterocyclyl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -heterocyclyl, where the heterocyclyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is tetrahydropyran-4-ylmethyl.
  • R 6 is heteroaralkyl (e.g., -C 1-6 alkylene-heteroaryl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -heteroaryl, where the heteroaryl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -pyridyl, where the pyridyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -pyridyl, where the pyridyl group is optionally substituted with one or two chloro groups.
  • R 6 is 2-chloro-pyridin-5-ylmethyl.
  • R 6 is substituted or unsubstituted aralkyl (e.g., -C 1-6 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 selected independently from the group consisting of fluoro, chloro, methyl, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH(CH 3 )-phenyl.
  • R 6 is -CH 2 -aryl, optionally substituted by one or more occurrences of R 65 , as defined above.
  • R 6 is -CH 2 -aryl, where the aryl group is naphthyl, optionally substituted by one or more occurrences of R 65 , as defined above.
  • R 6 is -CH 2 -(2-naphthyl), -CH 2 -(1-naphthyl), or -CH(CH 3 ) 2 - naphthyl, where the naphthyl group is optionally substituted one or more times with substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • R 6 is -CH 2 -(2-naphthyl).
  • 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 -CH 2 -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, -SO 2 -CH 3 , -CO 2 CH 3 , -CO 2 H, trifluoromethyl,
  • R 6 is 3,4-dichlorobenzyl, 2,4-dichlorobenzyl, 4- (methanesulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 2-chloro-4-fluorobenzyl, 4- fluorobenzyl, 2,4-difluorobenzyl, 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
  • R 8a and R 8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR 81 , halogen, and cyano.
  • R 8a is hydrogen
  • R 8a is not hydrogen
  • R 8a is -OH or -O-R 81 .
  • R 81 is alkyl, e.g., methyl or ethyl.
  • 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
  • R 8b is not hydrogen. In certain embodiments, R 8b is -OH or -O-R 81 . In certain exemplary embodiments, R 81 is alkyl, e.g., methyl or ethyl.
  • 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 and R 8b are each hydrogen.
  • R 9a and R 9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OH, -OR 91 , -NH 2 , -NH-R 91 , -NR 91 R 92 , -C(O)-R 91 , -CO 2 H, -C(O)-O-R 91 , C(O)-NH 2 , -C(O)-NH-R 91 , -C(O)-NR 91 R 92 , -SO 2 -R 91 , -SO 2 -NH 2 , -SO 2 -NH-R 91 , -SO 2 - NR 91 R 92 , halogen, and cyano, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OH
  • R 9a and R 9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR 91 , halogen, and cyano.
  • At least one of R 9a and R 9b represents -OR 91 .
  • R 91 represents alkyl.
  • 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 , -CO 2 H, -C(O)-O-R 101 , -O-C(O)-R 101 , O-C(O)-OR 101 , -C(O)- NH 2 , -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.
  • R 9a is -OH or -O-R 91 .
  • R 9a is -O-R 91 .
  • R 91 is C 1-4 alkyl, e.g., methyl.
  • R 9a is halogen, e.g., bromo or chloro.
  • R 9a is C 1-6 alkyl, e.g., methyl, ethyl, or isopropyl.
  • R 9a is C 2-6 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 aryl, e.g., 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)- NH 2 , -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, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
  • R 9a is aryl, e.g., phenyl, optionally substituted with one or more substituents R 95 , wherein each occurrence of R 95 is independently selected from chloro, fluoro, C 1-6 alkyl, -O-R 91 , -CO 2 H, -CO 2 -R 91 , -S(O) 2 -R 91 , and hydroxyl, and R 91 is C 1 -C 6 alkyl C 1 -C 6 haloalkyl. In certain preferred embodiments, R 95 is fluoro or hydroxy.
  • 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. In certain such embodiments, R 95 is methyl.
  • R 9b is hydrogen. In other embodiments, R 9b is not hydrogen.
  • R 9b is -OH or -O-R 91 .
  • R 9b is -O-R 91 .
  • R 91 is C 1-4 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–CO 2 H.
  • 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 9b is C 3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.
  • R 9b is aryl, e.g., phenyl, optionally substituted with one or more substituents R 95 wherein: R 95 , independently for each occurrence, 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)- NH 2
  • 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 aryl, e.g., phenyl, optionally substituted with one or more substituents R 95 , wherein each occurrence of R 95 is independently selected from chloro, fluoro, C 1-6 alkyl, -O-R 91 , -CO 2 H, -CO 2 -R 91 , -S(O) 2 -R 91 , and hydroxyl, and R 91 is C 1 -C 6 alkyl C 1 -C 6 haloalkyl.
  • R 95 is fluoro, chloro, methoxy, or methanesulfonyl.
  • R 9b is 4-fluorophenyl, 4- chlorophenyl, 4-(methanesulfonyl)-phenyl, 2-methoxyphenyl, cyano, or -NO 2 .
  • R 9b is heteroaryl, optionally substituted by 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 .
  • compounds of the invention may be prodrugs of the compounds of Formula I or Formula II, 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.
  • the present invention relates to methods of treating or preventing cancer with a compound of Formula I or Formula II, 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 or II).
  • 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 or II).
  • 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 Formula II, 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 and Formula II are depicted in Table 1.
  • the compounds of Table 1 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.
  • the invention provides methods of treating cancer, comprising administering to a subject a compound of Formula I or Formula II, 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 Parenchymal Tumors of Intermediate Differentiation, Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma), Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Basal Cell
  • Bile Duct Cancer including Extrahepatic
  • Bladder Cancer including Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Carcinoid Tumor,
  • 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.
  • 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 (PE)
  • 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 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, mut
  • 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 2.
  • Table 2 Exemplary combinatorial therapies for the treatment of cancer.
  • n ceran emo mens e conon y amnsere cemo erapeu c agen s selected from 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.
  • 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 immune-oncology therapeutic, such as an inhibitor of arginase, CTLA-4, indoleamine 2,3- dioxygenase, and/or PD-1/PD-L1.
  • conjoint administration of the hexokinase II inhibitor(s) of Formula I or Formula II 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 II) 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 Formula I or Formula II 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 Formula II.
  • the invention also provides methods of inhibiting hexokinase activity in a cell, comprising contacting a cell with a compound of of Formula I or Formula II.
  • 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.
  • kits comprising: a) a pharmaceutical formulation (e.g., one or more single dosage forms) comprising a compound of the invention; and
  • 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; and (21) 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.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an 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 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), surface-active or dispersing agent.
  • 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 as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl
  • 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.
  • 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. In addition, 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.
  • various antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • 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.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
  • 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 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 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 Formula II.
  • 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 Formula II 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.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • 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.
  • 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 C 1 -C 6 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, -CF 3 , -CN, and the like.
  • C x-y when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • C x-y alkyl 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.
  • C 0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • C 2-y alkenyl and“C 2- 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.
  • the term“fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • the second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings.
  • 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.
  • esters 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.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy 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 -OSO 3 H, or a pharmaceutically acceptable salt thereof.
  • 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 SO 3 H, 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).
  • 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 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 were 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 autosampler using a Sepax GP-C18, 4.6 x 50 mm; 5 micron particle-size column.
  • a three minute gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B.
  • the system was interfaced with a Waters Micromass ZQ mass spectrometer using electrospray ionization. MassLynx software was employed. All MS data were obtained in the positive mode unless otherwise noted. The reported m/z data are generally accurate within about ⁇ 1 for the M+ ion.
  • NMP N-methylpyrrolidinone
  • Step 1 An indole derivative (20 mmol) is dissolved in DCM (15 mL) and pyridine (40 mmol) was added. The solution is cooled to about 0 ⁇ C, and a solution of
  • Step 1 The indole derivative (20 mmol) is dissolved in DCM (15 ml) and pyridine (40 mmol) is added. The solution is cooled to 0 ⁇ C (ice bath) as a solution of trichloroacetyl chloride (20 mmol) in DCM (5 ml) is added over the course of 30 minutes. The cooling bath is removed and the reaction mixture is stirred at room temperature overnight. All the volatiles are removed under reduced pressure. The crude product is stirred with ethanol- water (1:1, 15 mL) for 10 minutes before the product is filtered off, dried, and used without any further purification.
  • the reaction mixture can be extracted with ethyl acetate and the organic phase separated and washed with water, 1.0 N HCl and brine. The organic layer is dried (Na 2 SO 4 ) and concentrated in vacuo to give a tricholoroacetyl indole derivative.
  • Step 2 To the tricholoroacetyl indole derivative (0.096 mmol) in NMP (0.20 ml) is added K 2 CO 3 (0.144 mmol) and an alkyl chloride or bromide (0.125 mmol) or an arylalkyl chloride or bromide (such as benzyl bromide or chloride), and the reaction mixture is stirred overnight at room temperature.
  • 6-Bromo-1H-indole-3-carboxylic acid 24 g was dissolved in THF and DMF. To this solution was added NaH (24 g) portion wise over a period of 30 min. Vigorous reaction was observed and the solution became brownish white suspension. To this solution was added the 2-bromomethyl naphthalene (27.6 g) portion wise over a period of 30 min. The mixture was heated at 60 o C for 3-4 h and was cooled. The reaction mixture was poured on to crushed ice and stirred. The aqueous layer was neutralized with 2N HCl to pH 5-6. The precipitated solid was filtered, washed with water and suspended in toluene 500 mL and evaporated.
  • Step 1 6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (5.9 g) and 2-tributylstannanyl-thiazole (7.1 g) were dissolved in DMF (30 mL) and the mixture was purged with nitrogen for 10 min. To this reaction mixture was added dichlorobis(triphenylphosphine) palladium (II) (0.89 g) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 80 o C for 3.0 h, cooled to rt, EtOAc (25 mL) and saturated KF solution (20 mL) were added.
  • Step 2 The above ester was dissolved in 1:1 THF:methanol (20 mL) and was added 2.0 N lithium hydroxide (5.0 mL). The mixture was heated at 90 ⁇ C overnight, cooled to rt, 1.0 N HCl (10 mL) was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo to give 1- naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (5.0 g).
  • Step 3 1-Naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (5.0 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid
  • 6-Methoxy-1H-indole-3-carboxylic acid (1.9 g) was treated with 3,4-dichlorobenzyl chloride (2.8 mL) according to General Procedure A to give 2.17 g of 1-(3,4-dichloro- benzyl)-6-methoxy-1H-indole-3-carboxylic acid.
  • Example 2 as shown in Table 1, was made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) value for this example is 482.9.
  • Example 3 Example 3:
  • 6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in THF (5 mL) and MeOH (2.5 mL). To this stirring solution, 2.0 mL of 2.0 N KOH was added and the reaction mixture stirred at 80 ⁇ C overnight. The reaction mixture was then allowed to cool to rt, and 1.0 N HCl was added (pH ⁇ 7), and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and was dried over Na 2 SO 4 . Concentration in vacuo gave 6-acetyl-1-(3,4-dichloro-benzyl)-1H- indole-3-carboxylic acid (0.15 g).
  • 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was prepared according to General Procedure E using 6-bromo-1-(3,4-dichloro- benzyl)-1H-indole-3-carboxylic acid methyl ester (0.20 g) and pyridine-3-boronic acid (0.19 g).
  • 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in 1:1 THF:methanol (10 mL) and was added 2.5 M sodium hydroxide (3 mL).
  • 1-(3,4-Dichloro-benzyl)-6-cyano-1H-indole-3-carboxylic acid (0.8 g) was prepared according to General Procedure A starting from 1H-indole-3-carboxylic acid (0.5 g) and 3,4-dichlorobenzylchloride (0.3 g).
  • Examples 13 to 46 were made by procedures analogous to those described above for Example 1.
  • the observed LCMS (m/z) values for these examples are as follows; Example 13: 480.9; Example 14: 481.0; Example 15: 510.7; Example 16: 510.8; Example 17: 510.9; Example 18: 491.0; Example 19: 481.0; Example 20: 448;
  • Example 21 465.5; Example 22: 431.0; Example 23: 449; Example 24: 443.0; Example 25: 495; Example 26: 477; Example 27: 497; Example 28: 479.8; Example 29: 471; Example 30: 501.0; Example 31: 543.0; Example 32: 592.0; Example 33: 443; Example 34: 479; Example 35: 480.7; Example 36: 443; Example 37: 413; Example 38: 467.6; Example 39: 520.7; Example 40: 500; Example 41: 526.7; Example 42: 554.8; Example 43: 578.8; Example 44: 587; Example 45: 506; Example 46: 525.6.
  • Examples 47 to 54 as shown in Table 1, were made by procedures analogous to those described above for Example 7.
  • Example 47 548.5; Example 48: 574.4; Example 49: 634.4; Example 50: 590.8; Example 51: 588.2; Example 52: 575.6; Example 53: 571.6; Example 54: 558.7.
  • Examples 55 to 60 as shown in Table 1, were made by procedures analogous to those described above for Example 1.
  • the observed LCMS (m/z) values for these examples are as follows; Example 55: 510.7; Example 56: 494.5; Example 57: 510.7; Example 58: 494.8; Example 59: 522.6; Example 60: 526.4.
  • Example 61 as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 7.
  • Example 62 as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 3.
  • the observed LCMS (m/z) value for this example is 560.4.
  • Examples 63 to 67 as shown in Table 1, were made by procedures analogous to those described above for Example 1.
  • the observed LCMS (m/z) values for these examples are as follows; Example 63: 448.5; Example 64: 456.5; Example 65: 442.7; Example 66: 408.7; Example 67: 450.7.
  • Examples 68 to 70 as shown in Table 1, were made by procedures analogous to those described above for Example 3.
  • Example 71 as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 7.
  • the observed LCMS (m/z) value for this example is 556.6.
  • Examples 72 to 75, as shown in Table 1, were made by procedures analogous to those described above for Example 4.
  • the observed LCMS (m/z) values for these examples are as follows; Example 72: 538.6; Example 73: 580.7; Example 74: 538.8; Example 75:
  • Example 76 to 78 were made by procedures analogous to those described above for Example 7.
  • the observed LCMS (m/z) values for these examples are as follows; Example 76: 586.7; Example 77: 587.6; Example 78: 585.6.
  • Examples 79 and 80 as shown in Table 1, were made by procedures analogous to those described above for Example 1.
  • the observed LCMS (m/z) values for these examples are as follows; Example 79: 518.7; Example 80: 492.8.
  • Example 81 as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 7.
  • the observed LCMS (m/z) value for this example is 506.6.
  • Example 82 as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 9.
  • the observed LCMS (m/z) value for this example is 508.8.
  • Example 83
  • 6-(3,5-Dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.35 g) was prepared according to General Procedure E using 6-bromo-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.70 g, intermedate 3) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (0.47 g).
  • 6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.27 g) was synthesized according to General Procedure B starting from 6- (3-methyl-[1,2,4]oxadiazol-5-yl)-1H-indole (0.4g).
  • 6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid methyl ester prepared according to General Procedure E using 1- naphthalen-2-ylmethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-3- carboxylic acid methyl ester (0.25g) and 2-bromo-5-methyl-[1,3,4]thiadiazole.
  • 6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.15 g) was synthesized according to General Procedure B starting from 6-(5-methyl- oxazol-2-yl)-1H-indole (0.6 g).
  • 6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.5 g) was synthesized according to General Procedure B starting from 6-benzyloxy-1-naphthalen-2- ylmethyl-1H-indole (8.7 g).
  • 6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.4 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.10 g).
  • Example 96 506.9 and Example 97: 499.9.
  • Example 98 as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 87.
  • the observed LCMS (m/z) value for this example is 529.8.
  • Example 99
  • Examples 103 and 104 were made by procedures analogous to those described above for Example 86.
  • the observed LCMS (m/z) values for these examples are as follows; Example 103: 559.7 and Example 104: 560.0.
  • Examples 105 and 106, as shown in Table 1, were made by procedures analogous to those described above for Example 1.
  • the observed LCMS (m/z) values for these examples are as follows; Example 105: 463.6; Example 106: 462.8.
  • Examples 107 as shown in Table 1, was made by procedures analogous to those described above for Example 86.
  • the observed LCMS (m/z) value for this example is 545.7.
  • Example 80 6-methoxy-1-naphthalen-2- ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-amide, following these steps:
  • Step 1 Example 80, 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R, 5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (4.92 g, 10.0 mmol) was dissolved in allyl alcohol (20 mL) and 2.5 mL hydrochloric acid (6.0 N solution in water) was added and the mixture was heated at 120 o C for 6 h.
  • allyl alcohol (20 mL)
  • hydrochloric acid 6.0 N solution in water
  • Step 2 The intermediate from step 1, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ((3R,4R,5S,6R)-2-allyloxy-4,5-dihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-amide. (4.7 g, 8.8 mmol) was dissolved in dry pyridine (10 mL) then cooled to 0 o C. To this solution p-toulenesulfonyl chloride (2.01 g, 10.6 mmol) was added and the mixture was stirred at 0 o C for 30 min then at rt for 6 h.
  • 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ((3R,4R,5S,6R)-2-allyloxy-4,5-dihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-amide. (4.7
  • Step 3 The intermediate from step 2, toluene-4-sulfonic acid (2R,3S,4R,5R)-6- allyloxy-3,4-dihydroxy-5-[(6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carbonyl)- amino]-tetrahydro-pyran-2-ylmethyl ester (4.3 g, 6.25 mmol) was dissolved in dry DMF (10 mL) and treated with sodium azide (1.97 g, 31.0 mmol). The reaction mixture was heated at 80 o C for 4h. The mixture was then poured into brine (50 mL) and extracted with EtOAc (100 mL). The organic phase was separated and concentrated under reduced pressure. The residue was purified via medium pressure silica gel chromatography (MPLC) using 20:80 to 50:50 EtOAc:DCM gradient as eluent to afford the azide intermediate (2.7 g). LCMS: m/z 558.
  • Step 4 The intermediate from step 3, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ((3R,4R, 5S,6R)-2-allyloxy-6-azidomethyl-4,5-dihydroxy- tetrahydro-pyran-3-yl)-amide (2.23 g, 4.0 mmol) was dissolved in THF (20 mL).
  • Triphenylphosphine (2.62 g, 10.0 mmol) was added at rt and the reaction mixture was stirred for 10 min. Water (2.0 mL) was added and the mixture was stirred at rt for 16 h. The mixture was then concentrated under reduced pressure and the residue was purified via medium pressure silica gel chromatography (MPLC) using 2-10% MeOH in 5% ammonia- DCM as eluent to afford the amine intermediate (1.8 g). LCMS: m/z 532.
  • Step 5 The intermediate from step 4, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ((3R, 4R, 5S, 6R)-2-allyloxy-6-aminomethyl-4,5-dihydroxy- tetrahydro-pyran-3-yl)-amide (106 mg, 0.2 mmol) was dissolved in EtOAc (5 mL) and treated with saturated NaHCO 3 solution (5 mL). Dichloroacetyl chloride (0.1 mL, 1.0 mmol) was added and the reaction mixture was stirred at rt for 6 h. The mixture was then poured into brine (10 mL) and extracted with EtOAc (20 mL).
  • Step 6 The intermediate from step 5, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ⁇ (3R,4R,5S,6R)-2-allyloxy-6-[(2,2-dichloro-acetylamino)- methyl]-4,5-dihydroxy-tetrahydro-pyran-3-yl ⁇ -amide (64 mg, 0.1 mmol) was dissolved in dry MeOH (2 mL) and palladium (II) chloride (18 mg, 0.1 mmol) was added. The reaction mixture was heated at 50 o C for 2h.
  • Step 1 1-(3,4-Dichlorobenzyl)-6-methoxy-1H-indole-3-carboxylic acid (2.56 g) was prepared according to General Procedure A using 6-methoxy-1H-indole-3-carboxylic acid (1.91 g) and 3,4-dichlorobenzyl chloride (2.80 mL). LCMS: m/z 349.9 Step 2: 1-(3,4-Dichlorobenzyl)-6-methoxy-1H-indole-3-carboxylic acid
  • Step 3 Acetic acid (3R,4R,5S,6R)-2,5-diacetoxy-6-acetoxymethyl-3- ⁇ [1-(3,4- dichlorobenzyl)-6-methoxy-1H-indole-3-carbonyl]-amino ⁇ -tetrahydro-pyran-4-yl ester (591 mg) was prepared according to General Procedure D using 1-(3,4-dichlorobenzyl)-6- methoxy-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-amide (511 mg).
  • LCMS m/z 678.7
  • Step 4 Acetic acid (3aR,5R,6S,7R,7aR)-7-acetoxy-5-acetoxymethyl-2-[1-(3,4- dichlorobenzyl)-6-methoxy-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-6- yl ester (235 mg) was prepared according to General Procedure P using acetic acid
  • Step 5 The title compound (42 mg) was prepared according to General Procedure Q using acetic acid (3aR,5R,6S,7R,7aR)-7-acetoxy-5-acetoxymethyl-2- [1-(3,4-dichlorobenzyl)-6-methoxy-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]oxazol-6-yl ester (62 mg).
  • LCMS m/z 492.7.
  • Step1 1-(3,4-Dichlorobenzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid (140 mg) was synthesized according to General Procedure R starting from 6-methanesulfonyl- 1H-indole (250 mg).
  • Step 2 1-(3,4-Dichloro-benzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid (140 mg) was reacted with alpha-D-glucosamine hydrochloride (83 mg) according to the General Procedure C to give 1-(3,4-dichlorobenzyl)-6-methanesulfonyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (60 mg).
  • LCMS m/z 558.3
  • Step 3 The title compound (8 mg) was prepared according to General Procedures D, P and Q starting from 1-(3,4-dichlorobenzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (20 mg).
  • LCMS m/z 540.5
  • Example 112 Example 112:
  • Step 1 Intermediate 1 (0.25 g) and 1-ethoxyvinyltripropyl-stannane (0.29 g) in DMF (5.0 mL) was purged with nitrogen (10 min). To this solution dichloro
  • Step 2 6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in THF (5 mL) and MeOH (2.5 mL). To this stirring solution 2.0 mL of 2.0 N KOH was added and reaction the mixture stirred at 80 ⁇ C overnight. The reaction mixture was allowed to cool to room temperature, and then 1.0 N HCl was added (pH ⁇ 7), and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried (Na 2 SO 4 ). Concentration in vacuo gave 6-acetyl-1-(3,4-dichloro-benzyl)- 1H-indole-3-carboxylic acid (0.15 g).
  • Step 3 6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid (89 mg) was treated with alpha-D-glucosamine hydrochloride (63 mg) according to the General
  • Step 4 The title compound (12 mg) was prepared according to General Procedures D, P and Q starting from 6-acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (25 mg).
  • LCMS m/z 504.5
  • Example 113 Example 113:
  • Step 1 1H-Indole-6-carboxylic acid (500 mg) was reacted with 2.0 M methylamine in MeOH (6.2 mL) according to the General Procedure C to give 1H-indole-6-carboxylic acid methyl amide (150 mg).
  • Step 2 1-(3,4-Dichloro-benzyl)-6-methylcarbamoyl-1H-indole-3-carboxylic acid (30 mg) was synthesized according to General Procedure R starting from 1H-indole-6- carboxylic acid methyl amide (150 mg).
  • Step 3 1-(3,4-Dichloro-benzyl)-6-methylcarbamoyl-1H-indole-3-carboxylic acid (20 mg) was treated with alpha-D-glucosamine hydrochloride (13 mg) according to the General Procedure C to give 1-(3,4-dichloro-benzyl)-1H-indole-3,6-dicarboxylic acid 6- methylamide 3-[((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide] (18 mg).
  • LCMS m/z 537.5
  • Step 4 The title compound (5 mg) was prepared according to General Procedures D, P and Q starting with 1-(3,4-dichloro-benzyl)-1H-indole-3,6-dicarboxylic acid 6- methylamide 3-[((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide] (16 mg).
  • LCMS m/z 519.7
  • Example 115 Example 115:
  • Step 1 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was prepared according to General Procedure E using Intermediate 1 (0.20 g) and pyridine-3-boronic acid (0.19 g).
  • Step 2 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in 1:1 THF:methanol (10 mL) and was treated with 2.5 M sodium hydroxide (3 mL). The mixture was heated at 60 ⁇ C overnight. The solution was concentrated in vacuo and the residue was neutralized to a pH of about 4 with 1N HCl. The mixture was extracted with ethyl acetate.
  • Step 3 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid (90 mg) was treated with alpha D-glucosamine hydrochloride (113 mg) according to General Procedure C to give 1-(3,4-dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (75 mg) LCMS (m/z): 557.9
  • Step 4 The title compound (16 mg) was prepared according to General Procedures D, P and Q starting from 1-(3,4-dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (35 mg).
  • LCMS m/z 539.7
  • Example 116 Example 116:
  • Step 1 6-Methoxy-1H-indole-3-carboxylic acid (150 mg) was treated with 2- bromomethyl-naphthalene (207 mg) according to the General Procedure A to give 6- methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (150 mg).
  • Step 2 6-Methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (50 mg) was treated with alpha-D-glucosamine hydrochloride (35 mg) according to the General Procedure C to give 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (35 mg).
  • LCMS m/z 492.8
  • Step 3 The title compound (7 mg) was prepared according to General Procedures D, P and Q starting from 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (15 mg).
  • LCMS m/z 474.8 Examples 117 to 125, as shown in Table 1, were made by procedures analogous to those described above for Example 110.
  • the observed LCMS (m/z) values for these examples are as follows; Example 126: 476.6; Example 127: 504.7.
  • Example 128 569.7; Example 129: 567.9; Example 130: 569.7; Example 131: 616.4; Example 132: 570.9.
  • Examples 133 to 141 as shown in Table 1, were made by procedures analogous to those described above for Example 116.
  • the observed LCMS(m/z) values for these examples are as follows; Example 133: 469; Example 134: 508.5; Example 135: 424.7; Example 136: 438.7; Example 137: 500.8; Example 138: 430.8; Example 139: 432.9; Example 140:
  • Example 142
  • 6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid methyl ester was prepared according to General Procedure E using 1- naphthalen-2-ylmethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-3- carboxylic acid methyl ester (0.25g) and 2-bromo-5-methyl-[1,3,4]thiadiazole.
  • 6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.12 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(5-methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl- 1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-yl)-amide (0.065 g).
  • 6-(3,5-dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.35 g) was prepared according to General Procedure E using 6-bromo-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.70 g, intermedate 3) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (0.47 g).
  • 6-(3,5-Dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.22g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(3,5-dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (0.19 g).
  • 6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (1.0 g, intermedate 2) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C. The residue was dissolved in DCM (5 ml), pyridine (5 ml) and then acetic anhydride (5.0 mL) was added.
  • 6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.5 g) was synthesized according to the General Procedure R starting from 6-benzyloxy-1-naphthalen- 2-ylmethyl-1H-indole (8.7 g).
  • 6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.4 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.10 g).
  • 6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.15 g) was synthesized according to the general procedure R starting from 6-(5-methyl- oxazol-2-yl)-1H-indole (0.6 g).
  • 6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.15 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(5-methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (0.070 g).
  • 6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.27 g) was synthesized according to General Procedure R starting from 6- (3-methyl-[1,2,4]oxadiazol-5-yl)-1H-indole (0.4g).
  • 6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.2 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl- 1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-yl)-amide (0.11 g).
  • Example 163 as shown in Table 1, was made by procedures analogous to those described above for Example 147.
  • the observed LCMS (m/z) value for this example is 541.8.
  • Examples 164 and 165 as shown in Table 1, were made by procedures analogous to those described above for Example 116.
  • the observed LCMS (m/z) values for these examples are as follows; Example 164: 478.9; Example 165: 490.9.
  • Step 1 The starting material amine (25 mg, 0.05 mmol) and pyridine (0.05 ml) in DCM (2 ml) was cooled to 0 o C then acetic anyhdride (0.25 mmol) was added to this solution at 0 o C and stirred for 4 h. After completion of the reaction, the mixture was poured into water (10 ml) and extratcted with EtOAc (20 ml) and concentrated to give the triacetate intermediate (21 mg). This intermediate was then subjected to next step without further purification.
  • Step 2 The title compound was prepared according to general procedure Q using the above intermediate from step 1 (21 mg) and ammonia (0.25 ml, 7.0 N in MeOH). LCMS: m/z 533.8 [M+1].
  • 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 MgCl 2 , 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).
  • ADP ADP concentration in ⁇ M.
  • RFUs were converted to ADP concentration ( ⁇ M) from the ADP standard curve.
  • a plot of ADP concentration ( ⁇ M) against log compound was generated, and IC 50 values were determined from plots using GraphPad PRISM according to the 4 parameter logistic equation Y Bottom+(Top- Bottom)/1+10 ⁇ ((Log(IC 50 )-X)*HillSlope)) where X is the logarithm of compound concentration and Y is ADP concentration in ⁇ M.
  • the antiproliferative activity of compounds was 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) were 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% O 2 , 5% CO 2 for 18-24 hours. Media was removed and replaced with 90 ⁇ L fresh media.
  • Compound (0.00001-100 ⁇ M) was diluted in media containing 3% DMSO and added to cells. Untreated cells or cells containing compound were 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 was 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 was measured using an IN Cell 2000 analyzer instrument with 10X objective.
  • the instrument setting for the Hoechst channel was excitation at 350 nm and emission at 455 nm.
  • the setting for the propidium iodide channel was excitation at 550 nm and emission at 605 nm.
  • the nuclei were counted in the Hoechst 33342 channel; the dead cells were counted in the propidium iodide channel.
  • Table 2 shows the results for various compounds tested in the HK2 Enzyme Assay, described above. Results are reported as the concentration at which the IC 50 was observed on the response curve.
  • Table 3 shows the results for various compounds tested in the HK2 Enzyme Assay, described above. Results are reported as the concentration at which the IC 50 was observed on the response curve. Table 3: HK2 Enzyme Assay
  • Table 4 shows the results for various compounds tested in the In Vitro Cell Proliferation Assay, described above. Results are reported as the concentration at which the IC 50 was observed on the response curve. Table 4: In Vitro Cell Proliferation Assay

Abstract

Provided herein are substituted fused oxazoline derivatives and substituted pyran derivatives useful as inhibitors of the HKII enzyme. The invention further provides pharmaceutical compositions of the compounds of the invention. The invention further provides medical uses of substituted fused oxazoline derivatives and substituted pyran derivatives, for example, as antitumor agents.

Description

Inhibitors of Hexokinase and Methods of Use Thereof Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No.62/171,051, filed June 4, 2015, which application is hereby incorporated by reference in its entirety. Background The Warburg Effect is a biochemical phenotype of certain types of malignant tumors. The effect, observed by Otto Warburg in the 1920s, describes the tendency of such tumors to metabolize glucose to lactic acid even when oxygen is present. Over expression of hexokinase II (HKII) is a general feature of tumors that exhibit the Warburg Effect, and is believed to play an important role in how these tumors survive and spread aggressively to surrounding tissue.
Inhibition of HKII 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. By interrupting the cells’ metabolism, 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.
There is therefore a continuing need to discover and develop new chemical entities that inhibit HKII and that may be useful as antitumor agents for administration to humans or other mammals. Summary of Invention In certain embodiments, the invention relates to compounds having the structure of Formula (I): - 1 -
Figure imgf000003_0001
and pharmaceutically acceptable salts thereof, wherein R1-R6, R8a, R8b, R9a, R9b, Z, and X1 are as defined in the specification.
In certain other embodiments, the invention relates to compounds having the structure of Formula (II):
Figure imgf000003_0002
and pharmaceutically acceptable salts thereof, wherein R3-R6, R8a, R8b, R9a, R9b, Z, and X1 are as defined in the specification.
In some embodiments, the invention relates to pharmaceutical compositions of a compound of Formula (I) or Formula (II), 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. Detailed Description of the Invention In certain aspects, the invention provides substituted pyran derivatives or substituted fused oxazoline derivatives, and pharmaceutical compositions thereof. In particular, such substituted pyran derivatives and fused oxazoline derivatives are useful as HKII inhibitors, and thus can be used as antitumor agents, antifungal agents, or an anti-angiogenesis inhibitors. I. COMPOUNDS
In certain embodiments, the invention relates to compounds having the structure of Formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
(I)
wherein:
R1 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
(heterocyclyl)alkyl, aralkyl, or heteroaralkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, and heteroaralkyl groups are optionally substituted;
R2 represents -OH;
R3 represents -OH, -O-R31, -NH2, -NH-R31, or NR31R32;
R4 represents -OH, -O-R41, -NH2, -NH-R41, or NR41R42;
R5 represents -G5-OH, -G5-O-R51, -G5-NH2, -G5-NH-R51, or -G5-NR51R52;
G5 represents -CRaRb-, -C(O)-, or a bond;
Z represents O, NH, NRZ1, or NC(O)RZ1;
X1 represents N or C-R7;
R6 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(O)-R61, -C(O)-OR61, -C(O)-NR61, -C(S)-R61,-C(S)-NR61, or -SO2-R61, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R7 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R71, -SH, -S- R71, -S(O)R71, -SO2-R71, -NH2, -NH-R71, -NR71R72, -C(O)-R71, -CO2H, -C(O)-O- R71, -O-C(O)-R71, -O-C(O)-OR71, -C(O)-NH2, -C(O)-NH-R71, -C(O)-NR71R72, -NH- C(O)-R71, -N(R72)-C(O)-R71, -NH-C(O)-NH2, -NH-C(O)-NHR71, -NH-C(O)- NR71R72, -N(R72)-C(O)-NH2, -N(R72)-C(O)-NHR71, -N(R72)-C(O)-NR71R72, -O- C(O)-NR71R72, -O-C(O)-NH-R71, -O-C(O)-NH2, -NH-C(O)-OR71, -N(R72)-C(O)- OR71, -SO2-NH2, -SO2-NH-R71, -SO2-NR71R72, -NH-SO2-R71, -N(R72)-SO2-R71, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; R8a and R8b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R81, -SH, -S-R81, -S(O)R81, -SO2-R81, -NH2, -NH-R81, - NR81R82, -C(O)-R81, -CO2H, -C(O)-O-R81, -O-C(O)-R81, -C(O)-NH2, -C(O)-NH- R81, -C(O)-NR81R82, -NH-C(O)-R81, -N(R82)-C(O)-R81, -NH-C(O)-NH2, -NH-C(O)- NHR81, -NH-C(O)-NR81R82, -N(R82)-C(O)-NH2, -N(R82)-C(O)-NHR81, -N(R82)- C(O)-NR81R82, -O-C(O)-NR81R82, -O-C(O)-NH-R81, -O-C(O)-NH2, -NH-C(O)- OR81, -N(R82)-C(O)-OR81, -SO2-NH2, -SO2-NH-R81, -SO2-NR81R82, -NH-SO2-R81, - N(R82)-SO2-R81, -C(S)-NH2, -C(S)-NH-R81, -C(S)-NR81R82, -NH-C(S)-R81, -N(R82)- C(S)-R81, -NH-C(S)-NH2, -NH-C(S)-NHR81, -NH-C(S)-NR81R82, -N(R82)-C(S)- NH2, -N(R82)-C(S)-NHR81, -N(R82)-C(S)-NR81R82, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,
(heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R9a and R9b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R91, -SH, -S-R91, -S(O)R91, -SO2-R91, -NH2, -NH-R91, - NR91R92, -C(O)-R91, -CO2H, -C(O)-O-R91, -O-C(O)-R91, -C(O)-NH2, -C(O)-NH- R91, -C(O)-NR91R92, -NH-C(O)-R91, -N(R92)-C(O)-R91, -NH-C(O)-NH2, -NH-C(O)- NHR91, -NH-C(O)-NR91R92, -N(R92)-C(O)-NH2, -N(R92)-C(O)-NHR91, -N(R92)- C(O)-NR91R92, -O-C(O)-NR91R92, -O-C(O)-NH-R91, -O-C(O)-NH2, -NH-C(O)- OR91, -N(R92)-C(O)-OR91, -SO2-NH2, -SO2-NH-R91, -SO2-NR91R92, -NH-SO2-R91, - N(R92)-SO2-R91, -C(S)-NH2, -C(S)-NH-R91, -C(S)-NR91R92, -NH-C(S)-R91, -N(R92)- C(S)-R91, -NH-C(S)-NH2, -NH-C(S)-NHR91, -NH-C(S)-NR91R92, -N(R92)-C(S)- NH2, -N(R92)-C(S)-NHR91, -N(R92)-C(S)-NR91R92, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,
(heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R61, R71, R72, R81, R82, R91, and R92 are each independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or R71 and R72, R81 and R82, or R91 and R92, 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;
R31, R32, R41, R42, R51, and R52 are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)- R103, -C(O)-NR103R104, and -SO2-R103, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and aralkyl groups are optionally substituted; and
R103 and R104 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
or R103 and R104, 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;
Ra and Rb are each independently selected from H, alkyl, (cycloalkyl)alkyl, aralkyl,
heteroaralkyl, alkenyl, and alkynyl; and
RZ1 represents alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, haloalkyl, alkoxy, or haloalkoxy.
In certain embodiments of the compound of Formula (I), R5 represents -G5-OH or - G5-O-R51.
In certain other embodiments of the invention, R5 represents -G5-NH2, -G5-NH-R51, or -G5-NR51R52.
In certain embodiments, optionally in combination with the embodiments described above, G5 represents -CRaRb-. Ra and Rb are each independently selected from H or a carbon-based substituent such as alkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, or alkynyl. For example, G5 can be -C(alkyl)2- or -CH(alkyl).
In certain preferred embodiments, G5 is -CH2-.
In alternative embodiments, G5 represents -C(O)-.
In certain preferred embodiments, R5 represents -CH2OH.
In certain embodiments, R5 represents -CH2-O-R51, wherein R51 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. In more specific embodiments, R51 can be 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, trifluoromethoxy. In certain preferred embodiments, R51 is methyl, ethyl, or isopropyl.
In certain embodiments, R5 represents -CH2-O-R51, wherein R51 is selected from - C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, and -SO2-R103. In certain preferred embodiments, R51 is -C(O)-R103. In certain such embodiments, R103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
In certain embodiments, R5 represents -CH2-NH2.
In certain embodiments, R5 represents -CH2NH-R51, and R51 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. In certain preferred embodiments, R51 is methyl, ethyl, or isopropyl.
In certain embodiments, R5 represents -CH2NH-R51 or -CH2NR51R52. In certain such embodiments, R51 and R52 are selected from -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)- R103, -C(O)-NR103R104, and -SO2-R103. In certain preferred embodiments, R5 represents - CH2NH-R51, wherein R51 is -C(O)-R103 or -SO2-R103.
In certain such embodiments, R103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
Alternatively, R103 represents 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.
In certain exemplary embodiments, R103 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.
In certain embodiments of the compound of Formula (I), R1 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl, optionally substituted at any position by one of more substituents R15, wherein: R15, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R1 represents methyl, ethyl, isopropyl, propyl, or butyl. In certain preferred embodiments, R1 represents H.
In certain embodiments, Z represents O or NH. In preferred embodiments, Z represents O.
In certain embodiments, R3 represents -O-R31, wherein R31 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy. In more specific embodiments, R31 can be 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, trifluoromethoxy. In certain preferred embodiments, R31 is methyl, ethyl, or isopropyl.
In certain embodiments, R3 represents -O-R31, wherein R31 is selected from -C(O)- R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, and -SO2-R103. In certain preferred embodiments, R31 is -C(O)-R103. In certain such embodiments, R103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
In certain preferred embodiments R3 represents -OH. In alternative embodiments, R3 represents -NH2 or -NH-R31, wherein R31 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. In certain preferred embodiments, R31 is methyl, ethyl, or isopropyl. Alternatively, R31 can be -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, or -SO2-R103, preferably -C(O)-R103 or -SO2-R103.
In certain such embodiments, R103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
In certain embodiments, R4 represents -O-R41, wherein R41 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy. In more specific embodiments, R41 can be 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, trifluoromethoxy. In certain preferred embodiments, R41 is methyl, ethyl, or isopropyl.
In certain embodiments, R4 represents -O-R41, wherein R41 is selected from -C(O)- R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, and -SO2-R103. In certain preferred embodiments, R41 is -C(O)-R103. In certain such embodiments, R103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
In certain preferred embodiments R4 represents -OH.
In alternative embodiments, R4 represents -NH2 or -NH-R41, wherein R41 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. In certain preferred embodiments, R41 is methyl, ethyl, or isopropyl. Alternatively, R41 can be -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, or -SO2-R103, preferably -C(O)-R103 or -SO2-R103.
In certain such embodiments, R103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
In certain preferred embodiments, R3 and R4 are both -OH. In certain embodiments, X1 represents N or CH.
In certain embodiments, X1 represents N.
In certain embodiments, X1 represents N, or CR7, wherein R7 represents hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R75, wherein:
R75, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, X1 represents N or CR7, wherein R7 represents -OH, -O- R71, -SH, -S-R71, -S(O)R71, -SO2-R71, -NH2, -NH-R71, -NR71R72, -C(O)-R71, -CO2H, -C(O)- O-R71, -O-C(O)-R71, -O-C(O)-OR71, -C(O)-NH2, -C(O)-NH-R71, -C(O)-NR71R72, -NH- C(O)-R71, -N(R72)-C(O)-R71, -NH-C(O)-NH2, -NH-C(O)-NHR71, -NH-C(O)-NR71R72, - N(R72)-C(O)-NH2, -N(R72)-C(O)-NHR71, -N(R72)-C(O)-NR71R72, -O-C(O)-NR71R72, -O- C(O)-NH-R71, -O-C(O)-NH2, -NH-C(O)-OR71, -N(R72)-C(O)-OR71, -SO2-NH2, -SO2-NH- R71, -SO2-NR71R72, -NH-SO2-R71, -N(R72)-SO2-R71, halogen, -NO2, or cyano.
In certain embodiments, X1 is CR7, wherein R7 represents lower alkyl, e.g., methyl, ethyl, or isopropyl.
In certain preferred embodiments of the compound of Formula (I), X1 represents CH.
In certain embodiments, R6 represents H. In certain embodiments, R6 represents -C(O)-R61, -C(O)-OR61, -C(O)-NR61, -C(S)- R61,-C(S)-NR61, or -SO2-R61, wherein R61 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
In certain embodiments, R6 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. In certain exemplary embodiments, R6 represents alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R65, wherein:
R65, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R6 represents substituted or unsubstituted (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl. In certain such embodiments, R6 is substituted at any position with one or more substituents R65, wherein R65 is defined above.
In certain embodiments, R6 represents substituted or unsubstituted -CH2-(1- naphthyl), -CH2-(2-naphthyl), or -CH2-(phenyl). In certain such embodiments, R6 is substituted at any position with one or more substituents R65, wherein R65 is defined above.
In certain more specific embodiments of the compounds of the invention described above, R65 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.
In more specific embodiments, R6 represents -CH2-(1-naphthyl), -CH2-(2-naphthyl), or -CH2-(phenyl), substituted at any position by one or more substituents R65, wherein each occurrence of R65 is independently selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
In certain embodiments, R6 is not hydrogen.
In certain embodiments, R6 is C1-6 alkyl, e.g., isobutyl.
In certain embodiments, R6 is (cycloalkyl)alkyl, e.g., -C1-6 alkylene-C3-10 cycloalkyl, where the alkylene and cycloalkyl groups are optionally substituted with one or more with substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-C3-10 cycloalkyl, where the cycloalkyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is cyclohexylmethyl.
In certain embodiments, R6 is (heterocyclyl)alkyl, (e.g., -C1-6 alkylene-heterocyclyl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-heterocyclyl, where the heterocyclyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is tetrahydropyran-4-ylmethyl.
In certain embodiments, R6 is heteroaralkyl (e.g., -C1-6 alkylene-heteroaryl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-heteroaryl, where the heteroaryl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-pyridyl, where the pyridyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain embodiments, R6 is -CH2-pyridyl, where the pyridyl group is optionally substituted with one or two chloro groups.
In certain embodiments, R6 is 2-chloro-pyridin-5-ylmethyl.
In certain embodiments, R6 is–CH2-benzothiazol-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is–CH2-benzofuran-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is–CH2-benzothiphene-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is–CH2-quinoxalin-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is–CH2-benzimidazol-2-yl, optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is substituted or unsubstituted aralkyl (e.g., -C1-6 alkylene-aryl). For example, aralkyl may be substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 is -CH(CH3)-aryl, optionally substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 is -CH(CH3)-phenyl, where the phenyl group is optionally substituted one or more times with substituents selected independently from the group consisting of fluoro, chloro, methyl, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH(CH3)-phenyl.
In certain embodiments, R6 is -CH2-aryl, optionally substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 is -CH2-aryl, where the aryl group is naphthyl, optionally substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 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 selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In exemplary embodiments, R6 is -CH2-(2-naphthyl).
In exemplary embodiments, R6 is -CH2-(1-naphthyl).
In certain embodiments, R6 is -CH2-phenyl, where the phenyl group is optionally substituted one or more times with substituents selected independently from R65. For example R6 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,
trifluoromethoxy, -SCF3, 3-methyl-1,2,4-oxadiazol-5-yl, 1,2,4-triazol-1-yl, morpholin-4-yl- sulfonyl, pyrazol-1-yl, -CN, phenyl, -O-C2-5 alkyl, and -C2-5 alkyl.
In exemplary embodiments, R6 is 3,4-dichlorobenzyl or 2,4-dichlorobenzyl.
In exemplary embodiments, R6 is 4-(methanesulfonyl)benzyl or 4- (trifluoromethyl)benzyl.
In exemplary embodiments, R6 is 2-chloro-4-fluorobenzyl or 4-fluorobenzyl.
In exemplary embodiments, R6 is 3-chloro-4-methoxy-benzyl or 4-isopropyl-benzyl. In exemplary embodiments, R6 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-cyanobenzyl, 2-(methanesulfonyl)-4-chlorobenzyl, 2,4-di(trifluoromethyl)- benzyl, 3,5-dichlorobenzyl, 3-chloro-4-fluorobenzyl, 2,5-dichlorobenzyl, 3-chloro-5- fluorobenzyl, 4-bromobenzyl or 3-phenyl-benzyl.
In certain embodiments of the invention, R8a and R8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR81, halogen, and cyano.
In certain embodiments, R8a is hydrogen.
In other embodiments, R8a is not hydrogen.
In certain embodiments, R8a is -OH or -O-R81.
In certain embodiments, R8a is -O-R81 or -O-C(O)R81. In certain such embodiments, R81 is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In certain exemplary embodiments, R81 is alkyl, e.g., methyl or ethyl. In certain embodiments, R8b is hydrogen.
In other embodiments, R8b is not hydrogen.
In certain embodiments, R8b is -OH or -O-R81.
In certain embodiments, R8b is -O-R81 or -O-C(O)R81. In certain such embodiments, R81 is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In certain exemplary embodiments, R81 is alkyl, e.g., methyl or ethyl. In other exemplary
embodiments, R8b is -O-benzyl.
In certain preferred embodiments, R8a and R8b are each hydrogen.
In certain embodiments, R9a and R9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR91, halogen, and cyano.
In certain preferred embodiments, at least one of R9a and R9b represents -OR91. In certain such embodiments, R91 represents alkyl.
In certain preferred embodiments, R9b represents -OR91. In certain such
embodiments, R91 represents alkyl.
In certain embodiments, R9a and R9b 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 R95, wherein:
R95, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and R101 and R102 independently for each occurrence represent substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R9a is hydrogen. In other embodiments, R9a is not hydrogen.
In certain embodiments, R9a is -OH or -O-R91.
In certain embodiments, R9a is -O-R91. In certain such embodiments, R91 is C1-4 alkyl, e.g., methyl.
In certain embodiments, R9a is halogen, e.g., bromo or chloro.
In certain embodiments, R9a is C1-6 alkyl, e.g., methyl, ethyl, or isopropyl.
In certain embodiments, R9a is C2-6 alkenyl, e.g., vinyl.
In certain embodiments, R9a is -C(O)-R91, -C(O)-NHR91, -S(O)2-R91,–C(O)-O-R91, or–CO2H, wherein R91 is -C1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R91 can be methyl, ethyl, or isopropyl.
In certain embodiments, R9a is C3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.
In certain embodiments, R9a is phenyl, optionally substituted with one or more substituents R95 wherein:
R95, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and R101 and R102 independently for each occurrence represent substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R9a is phenyl, optionally substituted with one or more substituents R95, wherein each occurrence of R95 is independently selected from chloro, fluoro, C1-6 alkyl, -O-R91, -CO2H, -CO2-R91, -S(O)2-R91, and hydroxyl, and R91 is C1-C6 alkyl C1-C6 haloalkyl.
In certain embodiments, R9a 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 R95 as described above. In certain such embodiments, R95 is methyl.
In certain embodiments, R9b is hydrogen. In other embodiments, R9b is not hydrogen.
In certain embodiments, R9b is -OH or -O-R91.
In certain embodiments, R9b is -O-R91.
In certain such embodiments, R91 is C1-4 alkyl, e.g., methyl, ethyl, isopropyl, or n- propyl.
In other such embodiments, R91 is -(CH2)2-OCH3.
In certain embodiments, R91 is C3-10 cycloalkyl, e.g., cyclohexyl.
In certain embodiments, R9b is halogen, e.g., bromo or chloro.
In certain embodiments R9b is C1-6 alkyl (e.g., methyl, ethyl, or isopropyl).
In certain embodiments, R9b is C2-6 alkenyl, e.g., vinyl.
In certain embodiments R9b is -C(O)-R91, -C(O)-NHR91, -S(O)2-R91,–C(O)-O-R91, and–CO2H. In certain such embodiments, R91 is -C1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R91 can be methyl, ethyl, or isopropyl.
In certain embodiments, R9b is C3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.
In certain embodiments, R9b is phenyl, optionally substituted with one or more substituents R95 wherein:
R95, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R9b is phenyl, optionally substituted with one or more substituents R95, wherein each occurrence of R95 is independently selected from chloro, fluoro, C1-6 alkyl, -O-R91, -CO2H, -CO2-R91, -S(O)2-R91, and hydroxyl, and R91 is C1-C6 alkyl C1-C6 haloalkyl.
In certain embodiments, R9b is 4-fluorophenyl, 4-chlorophenyl, 4- (methanesulfonyl)-phenyl, 2-methoxyphenyl, cyano, or -NO2.
In certain embodiments, R9b is heteroaryl, optionally substituted by one or more occurrences of R95 as described above.
In certain embodiments, R9b 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,
[1,3,4]thiadiazol-5-yl, optionally substituted with one or more occurrences of R95 as described above. In certain such embodiments, R95 is methyl.
In certain embodiments, R9b 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.
In certain embodiments, R9b 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)-NH2.
In certain embodiments, at least one of R6, R8a, R8b, R9a, and R9b is not H. In other embodiments, the invention relates to compounds having the structure of Formula (II), or a pharmaceutically acceptable salt thereof:
Figure imgf000019_0001
wherein:
R3 represents -OH, -O-R31, -NH2, -NH-R31, or NR31R32;
R4 represents -OH, -O-R41, -NH2, -NH-R41, or NR41R42;
R5 represents -G5-OH, -G5-O-R51, -G5-NH2, -G5-NH-R51, or -G5-NR51R52;
G5 represents -CRaRb-, -C(O)-, or a bond;
Z represents O, NH, NRZ1, or NC(O)RZ1;
X1 represents N or C-R7;
R6 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(O)-R61, -C(O)-OR61, -C(O)-NR61, -C(S)-R61, -C(S)-NR61, or -SO2-R61, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R7 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R71, -SH, -S- R71, -S(O)R71, -SO2-R71, -NH2, -NH-R71, -NR71R72, -C(O)-R71, -CO2H, -C(O)-O- R71, -O-C(O)-R71, -O-C(O)-OR71, -C(O)-NH2, -C(O)-NH-R71, -C(O)-NR71R72, -NH- C(O)-R71, -N(R72)-C(O)-R71, -NH-C(O)-NH2, -NH-C(O)-NHR71, -NH-C(O)- NR71R72, -N(R72)-C(O)-NH2, -N(R72)-C(O)-NHR71, -N(R72)-C(O)-NR71R72, -O- C(O)-NR71R72, -O-C(O)-NH-R71, -O-C(O)-NH2, -NH-C(O)-OR71, -N(R72)-C(O)- OR71, -SO 2
2-NH2, -SO2-NH-R71, -SO2-NR71R7 , -NH-SO2-R71, -N(R72)-SO2-R71, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R8a and R8b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R81, -SH, -S-R81, -S(O)R81, -SO2-R81, -NH2, -NH-R81, - NR81R82, -C(O)-R81, -CO2H, -C(O)-O-R81, -O-C(O)-R81, -C(O)-NH2, -C(O)-NH- R81, -C(O)-NR81R82, -NH-C(O)-R81, -N(R82)-C(O)-R81, -NH-C(O)-NH2, -NH-C(O)- NHR81, -NH-C(O)-NR81R82, -N(R82)-C(O)-NH2, -N(R82)-C(O)-NHR81, -N(R82)- C(O)-NR81R82, -O-C(O)-NR81R82, -O-C(O)-NH-R81, -O-C(O)-NH2, -NH-C(O)- OR81, -N(R82)-C(O)-OR81, -SO2-NH2, -SO2-NH-R81, -SO2-NR81R82, -NH-SO2-R81, -N(R82)-SO2-R81, -C(S)-NH2, -C(S)-NH-R81, -C(S)-NR81R82, -NH-C(S)-R81, - N(R82)-C(S)-R81, -NH-C(S)-NH2, -NH-C(S)-NHR81, -NH-C(S)-NR81R82, -N(R82)- C(S)-NH2, -N(R82)-C(S)-NHR81, -N(R82)-C(S)-NR81R82, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R9a and R9b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R91, -SH, -S-R91, -S(O)R91, -SO2-R91, -NH2, -NH-R91, - NR91R92, -C(O)-R91, -CO2H, -C(O)-O-R91, -O-C(O)-R91, -C(O)-NH2, -C(O)-NH- R91, -C(O)-NR91R92, -NH-C(O)-R91, -N(R92)-C(O)-R91, -NH-C(O)-NH2, -NH-C(O)- NHR91, -NH-C(O)-NR91R92, -N(R92)-C(O)-NH2, -N(R92)-C(O)-NHR91, -N(R92)- C(O)-NR91R92, -O-C(O)-NR91R92, -O-C(O)-NH-R91, -O-C(O)-NH2, -NH-C(O)- OR91, -N(R92)-C(O)-OR91, -SO2-NH2, -SO2-NH-R91, -SO2-NR91R92, -NH-SO2-R91, -N(R92)-SO2-R91, -C(S)-NH2, -C(S)-NH-R91, -C(S)-NR91R92, -NH-C(S)-R91, - N(R92)-C(S)-R91, -NH-C(S)-NH2, -NH-C(S)-NHR91, -NH-C(S)-NR91R92, -N(R92)- C(S)-NH2, -N(R92)-C(S)-NHR91, -N(R92)-C(S)-NR91R92, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R61, R71, R72, R81, R82, R91, and R92 are each independently selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl,;
or R71 and R72, R81 and R82, or R91 and R92, 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;
R31, R32, R41, R42, R51, and R52 are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)- R103, -C(O)-NR103R104, and -SO2-R103, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and aralkyl groups are optionally substituted;
R103 and R104 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or (cycloalkyl)alkyl;
or R103 and R104, 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;
Ra and Rb are each independently selected from H, alkyl, (cycloalkyl)alkyl, aralkyl,
heteroaralkyl, alkenyl, and alkynyl; and
RZ1 represents alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, haloalkyl, alkoxy, or haloalkoxy;
wherein at least one of R6, R8a, R8b, R9a, and R9b is not hydrogen.
In certain embodiments of the compound of Formula (II), Z represents O or NH. In preferred embodiments, Z represents O.
In certain embodiments of the compound of Formula (II), X1 represents N or CH. In certain embodiments, X1 represents N.
In certain embodiments, X1 represents N, or CR7, wherein R7 represents hydrogen or alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R75, wherein:
R75, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and R101 and R102 independently for each occurrence represent substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, X1 represents N or CR7, wherein R7 represents -OH, -O- R71, -SH, -S-R71, -S(O)R71, -SO2-R71, -NH2, -NH-R71, -NR71R72, -C(O)-R71, -CO2H, -C(O)- O-R71, -O-C(O)-R71, -O-C(O)-OR71, -C(O)-NH2, -C(O)-NH-R71, -C(O)-NR71R72, -NH- C(O)-R71, -N(R72)-C(O)-R71, -NH-C(O)-NH2, -NH-C(O)-NHR71, -NH-C(O)-NR71R72, - N(R72)-C(O)-NH2, -N(R72)-C(O)-NHR71, -N(R72)-C(O)-NR71R72, -O-C(O)-NR71R72, -O- C(O)-NH-R71, -O-C(O)-NH2, -NH-C(O)-OR71, -N(R72)-C(O)-OR71, -SO2-NH2, -SO2-NH- R71, -SO2-NR71R72, -NH-SO2-R71, -N(R72)-SO2-R71, halogen, -NO2, or cyano.
In certain embodiments, X1 is CR7, wherein R7 represents lower alkyl, e.g., methyl, ethyl, isopropyl, or butyl.
In certain preferred embodiments of the compound of Formula (II), X1 represents CH.
In certain embodiments, R3 represents -OH or -O-R31, and R4 represents -OH or -O- R41.
In certain embodiments, R3 represents -OH or -O-R31, wherein R31 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy. In more specific embodiments, R31 can be 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, trifluoromethoxy. In certain preferred embodiments, R31 is methyl, ethyl, or isopropyl.
In certain embodiments, R3 represents -OH or -O-R31, wherein R31 is selected from - C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, and -SO2-R103. In certain preferred embodiments, R31 is -C(O)-R103. In certain such embodiments, R103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
In certain preferred embodiments R3 represents -OH.
In alternative embodiments, R3 represents -NH2 or -NH-R31, wherein R31 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. In certain preferred embodiments, R31 is methyl, ethyl, or isopropyl. Alternatively, R31 can be -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, or -SO2-R103, preferably -C(O)-R103 or -SO2-R103.
In certain such embodiments, R103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
In certain embodiments, R4 represents -OH or -O-R41, wherein R41 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy. In more specific embodiments, R41 can be 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, trifluoromethoxy. In certain preferred embodiments, R41 is methyl, ethyl, or isopropyl.
In certain embodiments, R4 represents -OH or -O-R41, wherein R41 is selected from - C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, and -SO2-R103. In certain preferred embodiments, R41 is -C(O)-R103. In certain such embodiments, R103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
In certain preferred embodiments R4 represents -OH.
In alternative embodiments, R4 represents -NH2 or -NH-R41, wherein R41 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. In certain preferred embodiments, R41 is methyl, ethyl, or isopropyl. Alternatively, R41 can be -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, or -SO2-R103, preferably -C(O)-R103 or -SO2-R103.
In certain such embodiments, R103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
In certain embodiments, R3 represents -O-R31 and R4 represents -O-R41, wherein R31 and R41 are each independently selected from alkyl, -C(O)-R103, and -SO2-R103, wherein R103 is as described above.
In certain preferred embodiments, R3 and R4 are both -OH. In certain embodiments of the compound of Formula (II), R5 represents -G5-OH or - G5-O-R51. Preferably, R5 represents -G5-OH.
In certain other embodiments of the invention, R5 represents -G5-NH2, -G5-NH-R51, or -G5-NR51R52. In certain embodiments, R5 represents -G5-NH2 or -G5-NH-R51.
Preferably, R5 represents -G5-NH2.
In certain embodiments, optionally in combination with the embodiments described above, G5 represents -CRaRb-. Ra and Rb are each independently selected from H or a carbon-based substituent such as alkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, or alkynyl. For example, G5 can be -C(alkyl)2- or -CH(alkyl).
In certain preferred embodiments, G5 is -CH2-.
In certain preferred embodiments, R5 represents -CH2OH.
In certain embodiments, R5 represents -G5-O-R51, e.g., -CH2-O-R51, wherein R51 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. In more specific embodiments, R51 can be 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, trifluoromethoxy. In certain preferred embodiments, R51 is methyl, ethyl, or isopropyl.
In certain embodiments, R5 represents -G5-O-R51, e.g., -CH2-O-R51, wherein R51 is selected from -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104, and -SO2- R103. In certain preferred embodiments, R51 is -C(O)-R103. In certain such embodiments, R103 is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.
In certain preferred embodiments, R5 represents -G5-O-R51, and R51 represents alkyl, -C(O)- R103, and -SO2-R103.
In certain embodiments, R5 represents -CH2-NH2.
In certain embodiments, R5 represents -CH2NH-R51, and R51 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. In certain preferred embodiments, R51 is methyl, ethyl, or isopropyl. In certain embodiments, R5 represents -CH2NH-R51 or -CH2NR51R52. In certain such embodiments, R51 and R52 are selected from -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)- R103, -C(O)-NR103R104, and -SO2-R103. In certain preferred embodiments, R5 represents - CH2NH-R51, wherein R51 is -C(O)-R103 or -SO2-R103. In other preferred embodiments, R5 represents -G5-NH-R51, and R51 represents alkyl, -C(O)-R103, and -SO2-R103.
In certain such embodiments, R103 is substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl.
Alternatively, R103 represents 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.
In certain exemplary embodiments, R103 represents isoxazolyl (e.g., isoxazol-5-yl), phenyl, imidazolyl (e.g., imidazol-4-yl), oxazolyl (e.g., 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.
In alternative embodiments, G5 represents -C(O)-.
In certain embodiments, R6 represents H.
In certain embodiments, R6 represents -C(O)-R61, -C(O)-OR61, -C(O)-NR61, -C(S)- R61,-C(S)-NR61, or -SO2-R61, wherein R61 is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
In certain embodiments, R6 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. In certain exemplary embodiments, R6 represents alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents R65, wherein:
R65, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R6 represents substituted or unsubstituted (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl. In certain such embodiments, R6 is substituted at any position with one or more substituents R65, wherein R65 is defined above.
In certain more specific embodiments of the compounds of the invention described above, R65 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. In still more specific embodiments, each occurrence of R65 is independently selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
In certain embodiments, R6 is not hydrogen.
In certain embodiments, R6 is C1-6 alkyl, e.g., isobutyl.
In certain embodiments, R6 is (cycloalkyl)alkyl (e.g., -C1-6 alkylene-C3-10 cycloalkyl), where the alkylene and cycloalkyl groups are optionally substituted with one or more with substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-C3-10 cycloalkyl, where the cycloalkyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is cyclohexylmethyl.
In certain embodiments, R6 is (heterocyclyl)alkyl (e.g., -C1-6 alkylene-heterocyclyl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain embodiments, R6 is -CH2-heterocyclyl, where the heterocyclyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, wherein R6 is tetrahydropyran-4-ylmethyl.
In certain embodiments, R6 is heteroaralkyl (e.g., -C1-6 alkylene-heteroaryl), optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-heteroaryl, where the heteroaryl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-pyridyl, where the pyridyl group is optionally substituted with one or more substituents selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH2-pyridyl, where the pyridyl group is optionally substituted with one or two chloro groups.
In certain embodiments, R6 is 2-chloro-pyridin-5-ylmethyl.
In certain embodiments, R6 is substituted or unsubstituted aralkyl (e.g., -C1-6 alkylene-aryl). For example, aralkyl may be substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 is -CH(CH3)-aryl, optionally substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 is -CH(CH3)-phenyl, where the phenyl group is optionally substituted one or more times with substituents selected independently from the group consisting of fluoro, chloro, methyl, hydroxy, trifluoromethyl, and trifluoromethoxy.
In certain embodiments, R6 is -CH(CH3)-phenyl.
In certain embodiments, R6 is -CH2-aryl, optionally substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 is -CH2-aryl, where the aryl group is naphthyl, optionally substituted by one or more occurrences of R65, as defined above.
In certain embodiments, R6 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 selected independently from the group consisting of fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In exemplary embodiments, R6 is -CH2-(2-naphthyl).
In exemplary embodiments, R6 is -CH2-(1-naphthyl).
In certain embodiments, R6 is -CH2-phenyl, where the phenyl group is optionally substituted one or more times with substituents selected independently from R65. For example R6 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,
trifluoromethoxy, -SCF3, 3-methyl-1,2,4-oxadiazol-5-yl, 1,2,4-triazol-1-yl, morpholin-4-yl- sulfonyl, pyrazol-1-yl, -CN, phenyl, -O-C2-5 alkyl, and -C2-5 alkyl.
In exemplary embodiments, R6 is 3,4-dichlorobenzyl, 2,4-dichlorobenzyl, 4- (methanesulfonyl)benzyl, 4-(trifluoromethyl)benzyl, 2-chloro-4-fluorobenzyl, 4- fluorobenzyl, 2,4-difluorobenzyl, 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-cyanobenzyl, 2-(methanesulfonyl)-4- chlorobenzyl, 2,4-di(trifluoromethyl)-benzyl, 3,5-dichlorobenzyl, 3-chloro-4-fluorobenzyl, 2,5-dichlorobenzyl, 3-chloro-5-fluorobenzyl, 4-bromobenzyl, 3-phenyl-benzyl, 4-phenyl- benzyl, 3-chloro-4-methoxy-benzyl or 4-isopropyl-benzyl.
In certain embodiments of the compound of Formula (II), R8a and R8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR81, halogen, and cyano.
In certain embodiments, R8a is hydrogen.
In other embodiments, R8a is not hydrogen.
In certain embodiments, R8a is -OH or -O-R81. In certain exemplary embodiments, R81 is alkyl, e.g., methyl or ethyl.
In certain embodiments, R8a is -O-R81 or -O-C(O)R81. In certain such embodiments, R81 is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In certain exemplary embodiments, R81 is alkyl, e.g., methyl or ethyl.
In certain embodiments, R8b is hydrogen.
In other embodiments, R8b is not hydrogen. In certain embodiments, R8b is -OH or -O-R81. In certain exemplary embodiments, R81 is alkyl, e.g., methyl or ethyl.
In certain embodiments, R8b is -O-R81 or -O-C(O)R81. In certain such embodiments, R81 is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In certain exemplary embodiments, R81 is alkyl, e.g., methyl or ethyl. In other exemplary
embodiments, R8b is -O-benzyl.
In certain preferred embodiments, R8a and R8b are each hydrogen.
In certain embodiments of the compound of Formula (II), R9a and R9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OH, -OR91, -NH2, -NH-R91, -NR91R92, -C(O)-R91, -CO2H, -C(O)-O-R91, C(O)-NH2, -C(O)-NH-R91, -C(O)-NR91R92, -SO2-R91, -SO2-NH2, -SO2-NH-R91, -SO2- NR91R92, halogen, and cyano, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted.
In certain embodiments, R9a and R9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR91, halogen, and cyano.
In certain preferred embodiments, at least one of R9a and R9b represents -OR91. In certain such embodiments, R91 represents alkyl.
In certain preferred embodiments, R9b represents -OR91. In certain such
embodiments, R91 represents alkyl.
In certain embodiments, R9a and R9b 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 R95, wherein:
R95, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R9a is hydrogen. In other embodiments, R9a is not hydrogen.
In certain embodiments, R9a is -OH or -O-R91.
In certain embodiments, R9a is -O-R91. In certain such embodiments, R91 is C1-4 alkyl, e.g., methyl.
In certain embodiments, R9a is halogen, e.g., bromo or chloro.
In certain embodiments, R9a is C1-6 alkyl, e.g., methyl, ethyl, or isopropyl.
In certain embodiments, R9a is C2-6 alkenyl, e.g., vinyl.
In certain embodiments, R9a is -C(O)-R91, -C(O)-NHR91, -S(O)2-R91,–C(O)-O-R91, or–CO2H, wherein R91 is -C1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R91 can be methyl, ethyl, or isopropyl.
In certain embodiments, R9a is C3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.
In certain embodiments, R9a is aryl, e.g., phenyl, optionally substituted with one or more substituents R95 wherein:
R95, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R9a is aryl, e.g., phenyl, optionally substituted with one or more substituents R95, wherein each occurrence of R95 is independently selected from chloro, fluoro, C1-6 alkyl, -O-R91, -CO2H, -CO2-R91, -S(O)2-R91, and hydroxyl, and R91 is C1-C6 alkyl C1-C6 haloalkyl. In certain preferred embodiments, R95 is fluoro or hydroxy.
In certain embodiments, R9a 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 R95 as described above. In certain such embodiments, R95 is methyl.
In certain embodiments, R9b is hydrogen. In other embodiments, R9b is not hydrogen.
In certain embodiments, R9b is -OH or -O-R91.
In certain embodiments, R9b is -O-R91.
In certain such embodiments, R91 is C1-4 alkyl, e.g., methyl, ethyl, isopropyl, or n- propyl.
In other such embodiments, R91 is -(CH2)2-OCH3.
In certain embodiments, R91 is C3-10 cycloalkyl, e.g., cyclohexyl.
In certain embodiments, R9b is halogen, e.g., bromo or chloro.
In certain embodiments R9b is C1-6 alkyl (e.g., methyl, ethyl, or isopropyl).
In certain embodiments, R9b is C2-6 alkenyl, e.g., vinyl.
In certain embodiments R9b is -C(O)-R91, -C(O)-NHR91, -S(O)2-R91,–C(O)-O-R91, and–CO2H. In certain such embodiments, R91 is -C1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R91 can be methyl, ethyl, or isopropyl.
In certain embodiments, R9b is C3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.
In certain embodiments, R9b is aryl, e.g., phenyl, optionally substituted with one or more substituents R95 wherein: R95, independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2-R101, -NH2, -NH-R101, - NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, O-C(O)-OR101, -C(O)- NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -NH- C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, -N(R102)-C(O)-NH2, - N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)-NR101R102, -O-C(O)-NH- R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)-OR101, -SO2-NH2, -SO2-NH- R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2-R101, halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
In certain embodiments, R9b is aryl, e.g., phenyl, optionally substituted with one or more substituents R95, wherein each occurrence of R95 is independently selected from chloro, fluoro, C1-6 alkyl, -O-R91, -CO2H, -CO2-R91, -S(O)2-R91, and hydroxyl, and R91 is C1-C6 alkyl C1-C6 haloalkyl. In certain embodiments, R95 is fluoro, chloro, methoxy, or methanesulfonyl.
In certain embodiments of the compound of the invention, R9b is 4-fluorophenyl, 4- chlorophenyl, 4-(methanesulfonyl)-phenyl, 2-methoxyphenyl, cyano, or -NO2.
In certain embodiments, R9b is heteroaryl, optionally substituted by R95 as described above.
In certain embodiments, R9b 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,
[1,3,4]thiadiazol-5-yl, optionally substituted with one or more occurrences of R95 as described above. In certain such embodiments, R95 is methyl.
In certain embodiments, R9b 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. In certain embodiments, R9b 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)-NH2.
In certain embodiments, compounds of the invention may be prodrugs of the compounds of Formula I or Formula II, 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. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, or carboxylic acid).
In certain embodiments, 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.
In certain embodiments, as as will be described in detail below, the present invention relates to methods of treating or preventing cancer with a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula I or II). 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. In certain embodiments, 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. For example, if 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.
In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula I or II). 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.
In certain embodiments, 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 Formula II, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient.
Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein.
Exemplary compounds of Formula I and Formula II are depicted in Table 1. The compounds of Table 1 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. In the chemical structures shown below, standard chemical abbreviations are sometimes used.
Table 1. Exemplary Compounds of Formula I and Formula II
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
H O -- - H O OH O tetrahydro-pyran-3-yl)-amide
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
amide NO2
Figure imgf000041_0001
Figure imgf000042_0001
O amide
Figure imgf000043_0001
O amide
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
- - -- - OH amide
Figure imgf000048_0001
H O OH O N , , , -,,-r yroxy-- hydroxymethyl-tetrahydro-pyran-3-yl)- O amide
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
pyrano[3,2-d]oxazole-6,7-diol
Figure imgf000054_0001
Ex. Structure Name
142
Toluene-4-sulfonic acid (3aR,5R,6S, 7R,7aR)-2-[1-(3,4-dichloro-benzyl)-6- methoxy-1H-indol-3-yl]-6,7- dihydroxy-5,6,7,7a-tetrahydro-3aH- pyrano[3,2-d]oxazol-5-ylmethyl ester 143
(3aR,5R,6S,7R,7aR)-5-Aminomethyl- 2-[1-(3,4-dichloro-benzyl)-6-methoxy- 1H-indol-3-yl]-5,6,7,7a-tetrahydro-
Figure imgf000055_0001
3aH-pyrano[3,2-d]oxazole-6,7-diol 144
O Cl
O Acetic acid (3aR,5R,6S,7R,7aR)-6- O O N
Cl acetoxy-5-acetoxymethyl-2-[1-(3,4- O N dichloro-benzyl)-6-methoxy-1H-indol- O O 3-yl]-5,6,7,7a-tetrahydro-3aH- O O
pyrano[3,2-d]oxazol-7-yl ester 145
Acetic acid (3aR,5R,6S,7R,7aR)-6- acetoxy-5-acetoxymethyl-2-[1-(2,4- dichloro-benzyl)-6-methoxy-1H-indol- 3-yl]-5,6,7,7a-tetrahydro-3aH-
Figure imgf000055_0002
pyrano[3,2-d]oxazol-7-yl ester 146
O Cl
O Acetic acid (3aR,5R,6S,7R,7aR)-6- O O N N
Cl acetoxy-5-acetoxymethyl-2-[1-(3,4- O N dichloro-benzyl)-6-methoxy-1H- O O indazol-3-yl]-5,6,7,7a-tetrahydro-3aH- O O
pyrano[3,2-d]oxazol-7-yl ester 147
O (3aR,5R,6S,7R,7aR)-5- H O O N Hydroxymethyl-2-[6-(5-methyl- H O N [1,3,4]thiadiazol-2-yl)-1-naphthalen-2- OH
S ylmethyl-1H-indol-3-yl]-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]oxazole- N
N 6,7-diol
148
(3aR,5R,6S,7R,7aR)-5- Hydroxymethyl-2-[6-methoxy-1-(1- naphthalen-2-yl-ethyl)-1H-indol-3-yl]- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2-
Figure imgf000055_0003
d]oxazole-6,7-diol
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
II. USES OF HEXOKINASE II INHIBITORS
In certain aspects, the invention provides methods of treating cancer, comprising administering to a subject a compound of Formula I or Formula II, e.g., in a therapeutically effective amount.
In certain embodiments, 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 Parenchymal Tumors of Intermediate Differentiation, Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma), Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Basal Cell
Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Carcinoid Tumor,
Carcinoma of Unknown Primary, Central Nervous System (such as Atypical
Teratoid/Rhabdoid Tumor, Embryonal Tumors and Lymphoma), Cervical Cancer,
Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic
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
Histiocytoma of Bone (including Malignant and Osteosarcoma) Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor (Extracranial, Extragonadal, Ovarian), Gestational Trophoblastic Tumor, Glioblastoma, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), Kaposi Sarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (including Acute Lymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML), Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer (Non-Small Cell and Small Cell), Lymphoma (AIDS-Related, Burkitt, Cutaneous T-Cell (Mycosis Fungoides and Sézary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System (CNS), Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic
Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes,
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), Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic Stomach (Gastric) Cancer, Supratentorial Primitive Neuroectodermal Tumors, T-Cell Lymphoma (Cutaneous, Mycosis Fungoides and Sézary Syndrome), Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational), Unknown Primary, Unusual Cancers of Childhood, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Waldenström Macroglobulinemia and Wilms Tumor.
In certain embodiments, 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.
In certain embodiments, the solid tumor is a highly glycolytic tumor.
In certain embodiments, the subject is a mammal, e.g., a human.
The methods of the invention may not be limited to treating any particular type of cancer or cancerous tumor. In some embodiments, 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. In general, highly glycolytic tumors are tumors that exhibit a high rate of glucose metabolism to synthesize high levels of ATP. In contrast, normal cells obtain most of their ATP from oxidative phosphorylation, with only about 10% of their ATP being generated by glycolysis. Procedures that may be suitably used to identify whether cancer cells are of a highly glycolytic phenotype may be found in U.S. Patent Application Publication No.2010/0203110, incorporated herein by reference. In some embodiments, highly glycolytic tumors comprise cells that obtain at least 40% or at least 50% of their ATP from glycolysis under aerobic conditions. In some embodiments, 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 µM, 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. In some embodiments, 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). In such
embodiments, standard solutions of FDG may be used in conducting standard procedures of conducting PET imaging of a tumor. In some such embodiments, 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.
In certain embodiments, the cancer is associated with tissue of the bladder, bone marrow, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, skin or thyroid.
In certain embodiments, the method of treating cancer further comprises conjointly administering radiation therapy.
In some embodiments, 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, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil and 5-fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK2206, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, pazopanib, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, romidepsin, selumetinib, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). For example, 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,
chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, 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, vinblastine, vincristine, vindesine, and vinorelbine. In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, dexamethasone, 5- fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In certain embodiments of the methods of the invention described herein, the chemotherapeutic agent conjointly administered with compounds of the invention is a taxane chemotherapeutic agent, such as paclitaxel or docetaxel. In certain embodiments of the methods of the invention described herein, the chemotherapeutic agent conjointly administered with compounds of the invention is doxorubicin. In certain embodiments of the methods of the invention described herein, a compound of the invention is administered conjointly with a taxane
chemotherapeutic agent (e.g., paclitaxel) and doxorubicin.
In certain embodiments, the chemotherapeutic agent is selected from
aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide,
bisphosphonate, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol,
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, vinblastine, vincristine, vindesine, and vinorelbine.
In certain embodiments, the methods include conjoint administration with 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.
Many combination therapies have been developed for the treatment of cancer. In certain embodiments, 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 2.
Table 2: Exemplary combinatorial therapies for the treatment of cancer.
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
n ceran emo mens, e conon y amnsere cemo erapeu c agen s selected from 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.
In some embodiments, the conjointly administered chemotherapeutic agent is an immune-oncology therapeutic, such as an inhibitor of arginase, CTLA-4, indoleamine 2,3- dioxygenase, and/or PD-1/PD-L1. In certain embodiments, conjoint administration of the hexokinase II inhibitor(s) of Formula I or Formula II with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the hexokinase II inhibitor (e.g., a compound of Formula I or II) or the one or more additional therapeutic agent(s). In certain such embodiments, 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). In certain embodiments, coadministration produces a synergistic effect.
In certain embodiments, the hexokinase II inhibitor and the one or more additional chemotherapeutic agents are administered simultaneously. In alternative embodiments, 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.
In another aspect, the invention may provide for the use of a compound of Formula I or Formula II to induce tumor-specific oxidative stress cell death. In an embodiment, the method comprises increasing the production of reactive oxygen species (such as free radical compounds) in tumor cells relative to normal cells. In another embodiment, 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.
In certain embodiments, 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 Formula II.
The invention also provides methods of inhibiting hexokinase activity in a cell, comprising contacting a cell with a compound of of Formula I or Formula II. In certain embodiments, the cell is a cancer cell. Such methods may be performed in vivo or in vitro. III. KITS
In certain embodiments, 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) a pharmaceutical formulation (e.g., one or more single dosage forms) comprising a compound of the invention; and
b) instructions for the administration of the pharmaceutical formulation, e.g., for
treating or preventing cancer.
In certain embodiments, 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. In certain embodiments, the kit further comprises a second pharmaceutical formulation (e.g., as one or more single dosage forms) comprising a chemotherapeutic agent as mentioned above.
The disclosure also provides kits for detecting whether a subject having a cancer is likely to be responsive to hexokinase inhibitors. The kit 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. Among other uses, 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.
Optionally, a kit 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
In certain embodiments, the present invention provides pharmaceutical
compositions comprising a compound of any preceding claim and a pharmaceutically acceptable carrier.
The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, 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. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), 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. Such 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.
The phrase "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.
The phrase "pharmaceutically acceptable carrier" as used herein means a
pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be
"acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as
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
suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
A pharmaceutical composition (preparation) 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
(including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, 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.
Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, 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.
To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), 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, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical 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), surface-active or dispersing agent. 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, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, 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. They 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
gastrointestinal tract, optionally, in a delayed manner. Examples of embedding
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. In addition to the active ingredient, 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.
Besides inert diluents, the oral compositions can also include 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.
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.
Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.
Alternatively or additionally, 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.
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. Such 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. If desired, 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).
The phrases "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.
Pharmaceutical 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.
Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention 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. 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.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of
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. In addition, 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.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.
Alternatively, 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.
Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other 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.
For use in the methods of this invention, 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. For example, 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. By “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
administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
In general, 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.
If desired, 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. In certain embodiments of the present invention, 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.
In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, 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). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, 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. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., compound of formula I or Ia) or the one or more additional therapeutic agent(s). In certain such embodiments, 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).
This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. The term “pharmaceutically acceptable salt” as used herein 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. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, 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 Formula II. As another example, 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 Formula II per molecule of tartaric acid.
In further embodiments, 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,
benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, 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, emulsifiers and lubricants, 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.
Examples of pharmaceutically acceptable antioxidants 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. V. DEFINITIONS
The term“acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
The term“acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula
hydrocarbylC(O)NH-.
The term“acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
The term“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.
The term“alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
The term“alkenyl”, as used herein, 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.
Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, 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.
Moreover, the term "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, if not otherwise specified, 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. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, 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), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
The term“Cx-y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term“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- yalkynyl” 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.
The term“alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group. The term“alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
The term“alkynyl”, as used herein, 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.
Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.
The term“amide”, as used herein, refers to a group
Figure imgf000085_0001
wherein each R10 independently represent a hydrogen or hydrocarbyl group, or two R10 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.
The terms“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
Figure imgf000085_0002
wherein each R10 independently represents a hydrogen or a hydrocarbyl group, or two R10 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.
The term“aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.
The term“aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.
The term“aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably 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.
The term“carbamate” is art-recognized and refers to a group
Figure imgf000086_0001
wherein R9 and R10 independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R9 and R10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The terms“carbocycle”, and“carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term 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. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to 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. The term“fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A“cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.
The term“carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.
The term“carbonate” is art-recognized and refers to a group -OCO2-R10, wherein R10 represents a hydrocarbyl group.
The term“carboxy”, as used herein, refers to a group represented by the
formula -CO2H.
The term“ester”, as used herein, refers to a group -C(O)OR10 wherein R10 represents a hydrocarbyl group.
The term“ether”, as used herein, 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.
Examples of 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.
The terms“halo” and“halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
The terms“hetaralkyl” and“heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.
The terms“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. The terms“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.
The term“heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
The terms“heterocyclyl”,“heterocycle”, and“heterocyclic” refer 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. The terms “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. For example, “heterocyclyl” encompasses both pyrrolidine and pyrrolidinone.
The term“heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.
The term“hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.
The term“hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.
The term“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. A“lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy 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).
As used herein, the term“oxo” refers to a carbonyl group. When 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. When a group is referred to as being substituted by an“oxo” group, this can mean that a carbonyl moiety (i.e., -C(=O)-) replaces a methylene unit (i.e., -CH2-).
The terms“polycyclyl”,“polycycle”, and“polycyclic” refer 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. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
The term“silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto.
The term“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. In a broad aspect, 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. For purposes of this invention, 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 moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an“aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
The term“sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
The term“sulfonamide” is art-recognized and refers to the group represented by the general formulae
Figure imgf000090_0001
wherein R9 and R10 independently represents hydrogen or hydrocarbyl, such as alkyl, or R9 and R10 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.
The term“sulfoxide” is art-recognized and refers to the group -S(O)-R10, wherein R10 represents a hydrocarbyl.
The term“sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.
The term“sulfone” is art-recognized and refers to the group -S(O)2-R10, wherein R10 represents a hydrocarbyl.
The term“thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.
The term“thioester”, as used herein, refers to a group -C(O)SR10 or -SC(O)R10 wherein R10 represents a hydrocarbyl.
The term“thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
The term“urea” is art-recognized and may be represented by the general formula
Figure imgf000091_0001
wherein R9 and R10 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R9 taken together with R10 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, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY. Representative 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. Representative 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, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.
As used herein, 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.
The term“treating” includes prophylactic and/or therapeutic treatments. The term “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 term“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. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain
embodiments, some or all of the compounds of formula I 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.
Examples
Examples of compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof having useful biological activity are listed by name above in Table 1. The ability of compounds Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof to inhibit HK2 and inhibit proliferation of cancer cells was established with the representative compounds of Formula (I) or Formula (II) listed in Tables 2, 3, and 4 using the assays described below. A. Chemical Syntheses
The general procedures used in the methods to prepare the compounds of the present invention are described below. General Experimental Section
LC-MS data were 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 autosampler using a Sepax GP-C18, 4.6 x 50 mm; 5 micron particle-size column. In general, a three minute gradient was run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The system was interfaced with a Waters Micromass ZQ mass spectrometer using electrospray ionization. MassLynx software was employed. All MS data were obtained in the positive mode unless otherwise noted. The reported m/z data are generally accurate within about ±1 for the M+ ion.
1H NMR data were obtained on a Varian Mercury 400 MHz spectrometer and chemical shifts were referenced using either the residual solvent proton signal (e.g., residual CHCl3 in CDCl3) or the TMS signal as an internal reference. Microwave heating procedures were used in some experiments and, in these cases, a DISCOVER microwave synthesis system (CEM, Matthews, NC, USA) was used which included the use of pressurized glass reaction vessels at elevated temperatures. Medium pressure liquid chromatography (MPLC) was performed using Teledyne Isco CombiFlash Companion and CombiFlash Rf instruments, monitoring elution by UV absorption at 215 and 24 nM.
All reagents and solvents including anhydrous solvents were commercially available and were used as received unless described otherwise. Any solutions of Grignard reagents and organolithium reagents were commercially available and were used as received and at the concentrations listed on their labels. Reactions were stirred using a magnetic stirring apparatus and magnetic stir bar in most cases. All reactions using air-sensitive reagents were run under inert gas. For reactions not heated using a microwave-generating apparatus, the reaction temperatures reported in the experimental section refer to the temperatures of an oil bath or cooling bath placed around a reaction vessel. For reactions performed using a microwave-generating apparatus, the temperatures refer to the temperatures reported by the microwave apparatus. Abbreviations
Below are definitions of some common abbreviations that are used in the specification. The specification may also employ other abbreviations whose meanings are well known in the relevant art. Cbz = benzyloxycarbonyl
DCM = dichloromethane
DIC = N,N’-diisopropylcarbodiimide
DIEA = diisopropylethylamine
DME = 1,2-dimethoxyethane
DMF = N,N'-dimethylformamide
DMSO = dimethylsulfoxide
EtOAc = ethyl acetate EtOH = ethanol
h or hr = hours(s)
1H NMR = proton NMR analysis
HBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCl = hydrochloric acid
LC/MS, LCMS = liquid chromatography- mass spectrometry analysis
MeOH = methanol
min = minute(s)
NMP = N-methylpyrrolidinone
rt = room temperature
TEA = triethylamine
THF = tetrahydrofuran
TLC = thin layer chromatography
M = molar concentration
N = normal concentration General Procedure A: Alkylation of 1H-Indole/Indazole Carboxylic Acid
To a solution of a 1H-indole/indazole carboxylic acid (20 mmol) in dry THF or DMF or DMSO (100 mL) is added slowly sodium hydride (60% dispersion in mineral oil, 60 mmol). To this mixture is added an alkyl bromide or chloride, or an aryl alkyl bromide or chloride (60 mmol), and the reaction mixture is heated to 50-60 ^C for 3 hr. The mixture is then cooled to rt and poured onto crushed ice and acidified with 2 N aqueous HCl to pH 4. The precipitate is collected, washed with water and dried. Alternatively, the reaction workup mixture is extracted with ethyl acetate. The organic layer is washed with water and brine, and is then dried over sodium sulfate and concentrated in vacuo to give an N- alkylated indole/indazole carboxylic acid. General Procedure B: Preparation of Indole Carboxylic Acids
Step 1: An indole derivative (20 mmol) is dissolved in DCM (15 mL) and pyridine (40 mmol) was added. The solution is cooled to about 0 ^C, and a solution of
trichloroacetyl chloride (20 mmol) in DCM (5 mL) is added over the course of about 30 minutes. 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 minutes, and the product is filtered off, dried and used without further purification. Alternatively, the reaction mixture is partitioned between water and ethyl acetate. The organic phase is washed with water, 1.0 N HCl, and brine. The organic layer is dried over Na2SO4 and concentrated under reduced pressure to give a trichloroacetyl indole derivative.
Step 2: To the trichloroacetyl indole derivative (0.096 mmol) in NMP (0.20 mL) is added K2CO3 (0.144 mmol) and alkyl chloride or bromide (0.125 mmol), and the reaction mixture is stirred overnight at rt. To the reaction mixture is added aqueous NaOH (0.10 mL, 4 N) and the reaction mixture is stirred overnight and then neutralized with 1.0 N HCl (pH = 7-7.5). The reaction mixture is then partitioned between water and ethyl acetate. The organic layer is washed with water and brine, and is then dried over Na2SO4 and
concentrated under reduced pressure to give an indole carboxylic acid. General Procedure C: HBTU Coupling
To a stirring solution of an amine hydrochloride (1 mmol), a carboxylic acid (1 mmol), and HBTU (1 mmol) in dry DMF (2 mL), is added DIEA (2 mmol). The reaction mixture is heated at 90 ^C for 1 hour. The reaction progress is monitored by TLC and/or LCMS. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography using a gradient of 2-10 % MeOH in DCM to give an amide. General Procedure D: Preparation of Pyranose Amide tetra-O-Acetate
To a solution of pyranose amide (0.5 mmol) in dry dichloromethane (2 mL) is added acetic anhydride (3 mmol) and pyridine (3 mmol). The reaction mixture is stirred at room temperate for 3-4 hr. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate and washed with water. The organic layer is concentrated in vacuo, and the residue is purified by silica gel flash chromatography using ethyl acetate in hexanes to give a pyranose amide tetra-O-acetate. General Procedure E: Suzuki Coupling
A bromo-indole (0.5 mmol), boronic acid (1.5 mmol), and Pd(Ph3)4 (10 mol%) are combined in a vial fitted with a rubber septum. This mixture is then evacuated and purged with nitrogen for about 20 minutes. To this mixture are added degassed DME (7 mL), EtOH (3 mL) and Na2CO3 solution (1.5 mL, 2 N). The mixture is then heated at 80 ^C overnight. The mixture is then diluted with ethyl acetate and the organic layer is washed with water and brine, and dried over Na2SO4. The organic layer is concentrated and the residue is purified by silica gel column chromatography to give the product. General Procedure F: Preparation of 2-Amino-Pyran-3-yl Amide
To a solution of pyranose amide tetra-O-acetate (0.5 mmol) is added an amine (5.0 mmol) in MeOH (2 mL) and the reaction mixture is heated at reflux for 2-24 hr. The mixture is concentrated in vacuo and the residue is purified by silica gel flash
chromatography using a gradient of 2-10 % MeOH in DCM to give an amino-substituted compound. General Procedure G: Preparation of Amides or Ureas
To a stirring solution of an amine (0.5 mmol) in THF (1.0 mL) is added acyl chloride (1 mmol) or carbamyl chloride (1.0 mmol) and pyridine (1.0 mmol) and the reaction mixture is stirred at rt for 3-12 hr. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography using MeOH in DCM to give an amide or urea. General Procedure H: Preparation of Sulfones
Sulfide (0.1 mmol) was dissolved in methanol (1.0 mL) and 50 wt. % hydrogen peroxide in water (1.0 mL) was added. The reaction mixture is heated at 80 ^C for 8-12 hr. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography using MeOH in DCM to give a sulfone. General Procedure I: Preparation of Sulfoxides
Sulfide (0.1 mmol) is dissolved in methanol (1.0 mL) and 50 wt% hydrogen peroxide in water (1.0 mL) is added. The reaction mixture is stirred at rt for 6-12 hr. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography using MeOH in DCM to give a sulfoxide. General Procedure J: Preparation of 2-Alkoxy or 2-Sulfanyl-Substituted Pyran-3-yl Amide To pyranosamide tetra-O-acetate (0.5 mmol) is added an alcohol or a thiol (2 mL) and boron trifluoride-diethyl etherate (1 mL), and the reaction mixture is heated at reflux for 3-24 hr. The mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate and washed with saturated NaHCO3 solution. The organic layer is then concentrated in vacuo, and the residue is purified by silica gel flash chromatography using MeOH in DCM to give an alkoxy or thio alkyl compound. General Procedure K: Preparation of 2-Alkylamino-Substituted Pyran-3-yl Amide
To a solution of pyranose amide or pyranose amide tetra-O-acetate (1.0 mmol) is added an alkyl amine (5.0 to 10 mmol) or alkyl amine hydrochloride (5.0 to 10 mmol) and potassium carbonate (5.0 to 10 mmol) in MeOH (2 mL). The reaction mixture is heated at reflux for 2-24 hr. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography using a gradient of 2-10 % MeOH in DCM to give a 2- alkylamino-substituted compound. General Procedure L: Preparation of 2-N-Imidazole or 2-N-Pyrazol-Substituted Pyran-3-yl Amide
To a solution of pyranose amide tetra-O-acetate (0.2 mmol) is added an imidazole or pyrazole (2.0 mmol) in MeOH (2 mL) and the reaction mixture is heated at reflux for 2-24 hr. The mixture is concentrated in vacuo and the residue is purified by silica gel flash chromatography using a gradient of 2-10 % MeOH in DCM to give a 2-N-imidazole or 2- N-pyrazole-substituted compound. General Procedure M: Preparation of 2-Substituted Pyran 3-yl Urea
To a solution of 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (1.0 mmol, 49 mg) in EtOAc (10 mL) and HCl solution (2.5 M, 5 mL) is added alkyl or aryl ureas (10.0 eq, 10 mmol) and the reaction mixture is heated to 80 oC while stirring for 24 h. The reaction mixture is poured into cold water (10 mL) then extracted with ethyl acetate (10 mL) and concentrated. The residue is then purified by silica gel flash chromatography using a gradient of 10-20% MeOH in DCM to give desired 2-subsituted pyran-3yl urea. General Procedure N: Deprotection of Cbz Group from 2-Substituted Pyran 3-yl Urea To a solution of Cbz protected 3-aminoglucopyranose urea (1.0 mmol) in MeOH (5 mL) is added palladium hydroxide on carbon (40 mg) and the reaction mixture is placed under hydrogen atmosphere with hydrogen-filled balloon and stirred at rt for 16 h. After completion of the reaction the mixture is filtered through with a plug of silica gel then concentrated to give the crude 2-subsituted pyran 3-yl urea. This urea is subjected to next coupling step without further purification. General Procedure O: Urea and Carbamate formation of 2-Amino Pyran 3-yl Amide To the suspension of 2-amino pyran 3-yl amide (1.0 mmol) in ethyl acetate-water (1:1 v/v, 10 mL) is added sodium bicarbonate (2.0 mmol) and alkyl or arylchloroformate or alkyl or arylcarbamoyl chloride (2.0 mmol). The reaction is stirred at rt for 4 to 6 hr (monitored by TLC and LCMS). Then the organic layer is separated and concentrated in vacuo. The residue is purified by silica gel flash chromatography using a gradient of 5-15% MeOH in DCM to give the desired 2-amino substituted urea or carbamate. General Procedure P: Preparation of Pyrano[3,2-d]oxazoline tri-O-Acetate
To pyranose amide tetra-O-acetate (0.2 mmol) is added acetic acid (2 mL) and 33% hydrogen bromide in acetic acid (1.0 mL). The mixture is stirred at room temperate for 2-3 hours. The mixture is diluted with ethyl acetate (20 mL) and neutralized with saturated sodium bicarbonate solution in water. The organic layer is then condensed, and the residue is purified by silica gel flash chromatography using ethyl acetate in hexanes to give pyrano[3,2-d]oxazoline tri-O-acetate. General Procedure Q: Preparation of Pyrano[3,2-d]oxazoline Derivatives
To pyrano[3,2-d]oxazoline tri-O-acetate (0.1 mmol) is added 7 M ammonia in methanol (1.0 mL) and the reaction mixture is stirred at room temperature for 3-5 hours. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography using methanol in dichloromethane to give a pyrano[3,2-d]oxazoline derivative. General Procedure R: Preparation of Indole Carboxylic Acids
Step 1: The indole derivative (20 mmol) is dissolved in DCM (15 ml) and pyridine (40 mmol) is added. The solution is cooled to 0 ^C (ice bath) as a solution of trichloroacetyl chloride (20 mmol) in DCM (5 ml) is added over the course of 30 minutes. The cooling bath is removed and the reaction mixture is stirred at room temperature overnight. All the volatiles are removed under reduced pressure. The crude product is stirred with ethanol- water (1:1, 15 mL) for 10 minutes before the product is filtered off, dried, and used without any further purification. Alternatively, the reaction mixture can be extracted with ethyl acetate and the organic phase separated and washed with water, 1.0 N HCl and brine. The organic layer is dried (Na2SO4) and concentrated in vacuo to give a tricholoroacetyl indole derivative. Step 2: To the tricholoroacetyl indole derivative (0.096 mmol) in NMP (0.20 ml) is added K2CO3 (0.144 mmol) and an alkyl chloride or bromide (0.125 mmol) or an arylalkyl chloride or bromide (such as benzyl bromide or chloride), and the reaction mixture is stirred overnight at room temperature. To the reaction mixture is added aqueous NaOH (0.10 mL, 4 N) and the reaction mixture is stirred overnight, then neutralized with 1.0 N HCl (pH = 7- 7.5). The mixture is extracted with ethyl acetate and the organic layer is washed with water and brine, and dried (Na2SO4) and evaporated in vacuo to give an indole carboxylic acid. Intermediate 1: 6-Bromo-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid methyl ester To a solution of 6-bromoindole (65 mmol) in 100 mL DCM was added pyridine (100 mmol). The mixture was cooled to 0 ºC. To this solution was added trichloroacetyl chloride (100 mmol) slowly over a period of 15 minutes. The mixture was stirred at rt overnight. The reaction mixture was concentrated to give a brown solid. The solid was suspended in ethanol (50 mL) and was treated with water (50 mL). The mixture was stirred for 10 minutes, and the solid was filtered and dried in vacuo. This solid was dissolved in NMP (150 mL) and was treated with K2CO3 (100 mmol) followed by 3,4-dichlorobenzyl chloride (100 mmol). The mixture was stirred at rt overnight. After completion of the reaction, a 4 N NaOH solution (100 mL) was added and the mixture was stirred overnight. The mixture was poured into water and acidified with 1 N HCl to a pH of 4. The precipitated solid was filtered. The solid was dried in vacuo to furnish 6-bromo-1-(3,4- dichloro-benzyl)-1H-indole-3-carboxylic acid.
The acid was then dissolved in methanol (100 mL). To this solution was added 2 M trimethylsilyldiazomethane in hexane (80 mmol). The mixture was stirred for 30 min and was concentrated to dryness. The residue was purified by silica gel column chromatography (hexane-EtOAc, 70:30) to give 16.5 g of 6-bromo-1-(3,4-dichloro-benzyl)-1H-indole-3- carboxylic acid methyl ester.1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.93 (d, 1H), 7.92 (d, 1H), 7.66 (d, 1H), 7.60 (d, 1H), 7.38 (dd, 1H), 7.22 (dd, 1H), 5.52 (s, 2H), 3.82 (s, 3H) ppm.
Intermediate 2 (6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid) and intermediate 3 (6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester) were synthesized according to the procedures described above for Intermediate 1, or were synthesized as described below. Intermediate 2: (6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid)
6-Bromo-1H-indole-3-carboxylic acid (24 g) was dissolved in THF and DMF. To this solution was added NaH (24 g) portion wise over a period of 30 min. Vigorous reaction was observed and the solution became brownish white suspension. To this solution was added the 2-bromomethyl naphthalene (27.6 g) portion wise over a period of 30 min. The mixture was heated at 60 oC for 3-4 h and was cooled. The reaction mixture was poured on to crushed ice and stirred. The aqueous layer was neutralized with 2N HCl to pH 5-6. The precipitated solid was filtered, washed with water and suspended in toluene 500 mL and evaporated. The solid was dried under vacuum over night to get 6-bromo-1-naphthalen-2- ylmethyl-1H-indole-3-carboxylic acid (Intermediate 2) as yellowish white solid (31 g). Intermediate 3: (6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester)
6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (Intermediate 2) (14 g) was disolved in DCM (50 mL) and was added DMF (0.5 mL). To this solution was added oxalyl chloride (9.45 g). The mixture was heated at 60 oC and stirred for 30 min. The reaction mixture was concentrated to dryness and the solid obtained was dissolved in toluene. The toluene layer was evaporated to dryness to get the acid chloride intermediate as a yellow solid. This solid was suspended in dry methanol (200 mL) and was heated to reflux for 12h. The reaction mixture was evaporated to dryness and product 6-bromo-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (Intermediate 3) was obtained as a white solid. LCMS (m/z): 395.5
A similar procedure was used to synthesize 5-bromo-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid methyl ester starting from 5-bromo-indole carboxylic acid. Intermediate 4: 1-Naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
Step 1: 6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (5.9 g) and 2-tributylstannanyl-thiazole (7.1 g) were dissolved in DMF (30 mL) and the mixture was purged with nitrogen for 10 min. To this reaction mixture was added dichlorobis(triphenylphosphine) palladium (II) (0.89 g) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 80 oC for 3.0 h, cooled to rt, EtOAc (25 mL) and saturated KF solution (20 mL) were added. The reaction mixture was stirred at rt for 30 min and filtered through celite. The organic layer was separated, washed with water , brine, dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel flash chromatgraphy using a gradient of 10-20 % EtOAc in hexanes to give 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid methyl ester.
Step 2: The above ester was dissolved in 1:1 THF:methanol (20 mL) and was added 2.0 N lithium hydroxide (5.0 mL). The mixture was heated at 90 ^C overnight, cooled to rt, 1.0 N HCl (10 mL) was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 1- naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (5.0 g).
Step 3: 1-Naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (5.0 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (3.5 g). LCMS (m/z): 546.0 Example 1:
1-(3,4-Dichloro-benzyl)-6-methoxy-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
6-Methoxy-1H-indole-3-carboxylic acid (1.9 g) was treated with 3,4-dichlorobenzyl chloride (2.8 mL) according to General Procedure A to give 2.17 g of 1-(3,4-dichloro- benzyl)-6-methoxy-1H-indole-3-carboxylic acid.
1-(3,4-Dichloro-benzyl)-6-methoxy-1H-indole-3-carboxylic acid (0.35 g) was reacted with alpha-D-glucosamine hydrochloride (0.215 g) according to General Procedure C to give 0.343 g of the title compound. LCMS: m/z 510.8. 1H NMR (400 MHz, CD3OD): δ 8.07 (s, 1H), 7.67 (d, 1H), 7.48 (d, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.13 (d, 1H), 6.87 (dd, 1H), 5.41 (s, 2H), 5.27 and 4.74 (m, 1H), 3.58– 4.09 (m, 8H), 3.41– 3.48 (m, 1H) ppm (resonances for heteroatomic protons (e.g., NH, OH ) are not visible). Example 2, as shown in Table 1, was made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) value for this example is 482.9. Example 3:
1-(3,4-Dichloro-benzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)- 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide 1-(3,4-Dichloro-benzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid (140 mg) was synthesized according to General Procedure B starting from 6-methanesulfonyl-1H- indole (0.25 g).
1-(3,4-Dichloro-benzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid (0.14 g) was reacted with alpha-D-glucosamine hydrochloride (0.083 g) according to General Procedure C to give 0.06 g of the title compound. LCMS: m/z 558.3. Example 4:
1-(3,4-Dichloro-benzyl)-6-ethoxy-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
To a stirring solution of 1H-indol-6-ol (0.5 g) in DMF (5.0 mL) at -20 ^C was added NaH (60% dispersion in oil, 0.18 g). The reaction mixture was warmed to rt and then ethyl bromide (0.81 g) was added and stirring continued for 90 minutes. The reaction mixture was poured into ice water (10 mL) and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure. Then, the residue was purified by sillica gel column chromatography using a gradient of 0-10% EtOAc in hexanes to give 6-ethoxy-1H-indole (0.336 g).
1-(3,4-Dichloro-benzyl)-6-ethoxy-1H-indole-3-carboxylic acid (0.30 g) was synthesized according to General Procedure B starting from 6-ethoxy-1H-indole (0.33 g).
1-(3,4-Dichloro-benzyl)-6-ethoxy-1H-indole-3-carboxylic acid (0.18 g) was treated with alpha-D-glucosamine hydrochloride (0.13 g) according to General Procedure C to give the title compound (60 mg). LCMS: m/z 524.5. Example 5:
6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
6-Bromo-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid methyl ester (0.25 g) and 1-ethoxyvinyltripropylstannane (0.29 g) in DMF (5.0 mL) was purged with nitrogen (10 min). To this solution dichlorobis(triphenylphosphine) palladium (II) (0.059 g) was added. The reaction mixture was degassed for 10 minutes and heated at 90 ^C overnight. The mixture was cooled to rt and EtOAc (10 mL) and 1.0 N HCl (10 mL) were added. The mixture was stirred at rt for 1 hour. To this mixture, 20 mL of 1.0 N KF solution was added and stirred for another 30 minutes. The organic layer was separated, washed with water and brine, and dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography using DCM as an eluent to give 6-acetyl-1-(3,4-dichloro-benzyl)-1H- indole-3-carboxylic acid methyl ester (0.20 g).
6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in THF (5 mL) and MeOH (2.5 mL). To this stirring solution, 2.0 mL of 2.0 N KOH was added and the reaction mixture stirred at 80 ^C overnight. The reaction mixture was then allowed to cool to rt, and 1.0 N HCl was added (pH ~ 7), and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and was dried over Na2SO4. Concentration in vacuo gave 6-acetyl-1-(3,4-dichloro-benzyl)-1H- indole-3-carboxylic acid (0.15 g).
6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid (89 mg) was treated with alpha-D-glucosamine hydrochloride (63 mg) according to General Procedure C to give the title compound (25 mg). LCMS: m/z 522.7. Example 6:
1-(3,4-Dichloro-benzyl)-1H-indole-3,6-dicarboxylic acid 6-methylamide 3- [((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide]
1H-Indole-6-carboxylic acid (500 mg) was reacted with 2.0 M methylamine in MeOH (6.2 mL) according to General Procedure C to give 1H-indole-6-carboxylic acid methyl amide (150 mg).
1-(3,4-Dichloro-benzyl)-6-methylcarbamoyl-1H-indole-3-carboxylic acid (30 mg) was synthesized according to General Procedure C starting from 1H-indole-6-carboxylic acid methyl amide (150 mg).
1-(3,4-Dichloro-benzyl)-6-methylcarbamoyl-1H-indole-3-carboxylic acid (20 mg) was reacted with alpha-D-glucosamine hydrochloride (13 mg) according to General Procedure C to give the title compound (18 mg). LCMS: m/z 537.5. Example 7:
1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was prepared according to General Procedure E using 6-bromo-1-(3,4-dichloro- benzyl)-1H-indole-3-carboxylic acid methyl ester (0.20 g) and pyridine-3-boronic acid (0.19 g). 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in 1:1 THF:methanol (10 mL) and was added 2.5 M sodium hydroxide (3 mL). The mixture was heated at 60 ^C overnight. The solution was concentrated and the residue was neutralized with 1 N HCl of pH 7. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried (Na2SO4) and concentrated in vacuo to give 1-(3,4-dichloro-benzyl)-6-pyridin-3-yl- 1H-indole-3-carboxylic acid (150 mg). LCMS m/z: 396.8.
1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid (90 mg) was treated with alpha D-glucosamine hydrochloride (113 mg) according to General Procedure C to give the title compound (75 mg). LCMS (m/z): 557.9. Example 8, as shown in Table 1, was made by procedures analogous to those described above for Example 7. The observed LCMS (m/z) value for this example is 546.7. Example 9:
6-Cyclopentyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
6-Cyclopent-1-enyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.025 g) was dissolved in THF (5.0 mL) and EtOAc (2.5 mL). To this solution a catalytic amount of 10% Pd/C (20 mg) was added and the solution was degassed. The mixture was then hydrogenated using a hydrogen-filled balloon for 45 minutes. The mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound (22 mg). LCMS: m/z 548.6. Example 10, as shown in Table 1, was made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) value for this example is 506. Example 11:
1-(3,4-Dichloro-benzyl)-6-(1H-tetrazol-5-yl)-1H-indole-3-carboxylic acid
(2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
1-(3,4-dichloro-benzyl)-6-cyano-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.13 g) was dissolved in dry toluene (2 mL) and was treated with trimethylsilyl azide (0.2 mL) and dibutyltin oxide (0.3 g). The reaction mixture was then refluxed for 16 hr. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel using MeOH-TEA-DCM (1:1:8) as the eluent to give the title compound (45 mg). LCMS: m/z 549. Example 12:
1-(3,4-Dichloro-benzyl)-6-(4-methyl-thiazol-2-yl)-1H-indole-3-carboxylic acid
(2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
1-(3,4-Dichloro-benzyl)-6-cyano-1H-indole-3-carboxylic acid (0.8 g) was prepared according to General Procedure A starting from 1H-indole-3-carboxylic acid (0.5 g) and 3,4-dichlorobenzylchloride (0.3 g).
1-(3,4-dichloro-benzyl)-6-cyano-1H-indole-3-carboxylic acid (0.175 g) was dissolved in ethanol (3 mL) and treated with diethyl dithiophosphate (0.3 mL). To this mixture, water (0.1 mL) was added and the mixture was refluxed for 16 hr. The reaction mixture was then allowed to cool to rt and the mixture was concentrated in vacuo to give 1- (3,4-dichloro-benzyl)-6-thiocarbamoyl-1H-indole-3-carboxylic acid (0.15 g), which was used in the next step without further purification. LCMS: m/z 378.6.
1-(3,4-dichloro-benzyl)-6-thiocarbamoyl-1H-indole-3-carboxylic acid (65 mg) was dissolved in dry DMF (1 mL) and treated with chloroacetone (0.25 mL). The reaction mixture was refluxed for 3 hr. The mixture was then allowed to cool to rt, was
concentrated in vacuo, and the residue was purified by silica gel flash column
chromatography using ethyl acetate:DCM (1:1) as the eluent to give 1-(3,4-dichloro- benzyl)-6-(4-methyl-thiazol-2-yl)-1H-indole-3-carboxylic acid (80 mg). LCMS: m/z 416.7.
1-(3,4-Dichloro-benzyl)-6-(4-methyl-thiazol-2-yl)-1H-indole-3-carboxylic acid ((2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.034 g) was prepared according to General Procedure C starting from 1-(3,4-dichloro-benzyl)-6- (4-methyl-thiazol-2-yl)-1H-indole-3-carboxylic acid (0.050 g) and alpha-D-glucosamine hydrochloride (0.021g). LCMS: m/z 579. Examples 13 to 46, as shown in Table 1, were made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) values for these examples are as follows; Example 13: 480.9; Example 14: 481.0; Example 15: 510.7; Example 16: 510.8; Example 17: 510.9; Example 18: 491.0; Example 19: 481.0; Example 20: 448;
Example 21: 465.5; Example 22: 431.0; Example 23: 449; Example 24: 443.0; Example 25: 495; Example 26: 477; Example 27: 497; Example 28: 479.8; Example 29: 471; Example 30: 501.0; Example 31: 543.0; Example 32: 592.0; Example 33: 443; Example 34: 479; Example 35: 480.7; Example 36: 443; Example 37: 413; Example 38: 467.6; Example 39: 520.7; Example 40: 500; Example 41: 526.7; Example 42: 554.8; Example 43: 578.8; Example 44: 587; Example 45: 506; Example 46: 525.6. Examples 47 to 54, as shown in Table 1, were made by procedures analogous to those described above for Example 7. The observed LCMS (m/z) values for these examples are as follows; Example 47: 548.5; Example 48: 574.4; Example 49: 634.4; Example 50: 590.8; Example 51: 588.2; Example 52: 575.6; Example 53: 571.6; Example 54: 558.7. Examples 55 to 60, as shown in Table 1, were made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) values for these examples are as follows; Example 55: 510.7; Example 56: 494.5; Example 57: 510.7; Example 58: 494.8; Example 59: 522.6; Example 60: 526.4. Example 61, as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 7. The observed LCMS (m/z) value for this example is 556.5. Example 62, as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 3. The observed LCMS (m/z) value for this example is 560.4. Examples 63 to 67, as shown in Table 1, were made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) values for these examples are as follows; Example 63: 448.5; Example 64: 456.5; Example 65: 442.7; Example 66: 408.7; Example 67: 450.7. Examples 68 to 70, as shown in Table 1, were made by procedures analogous to those described above for Example 3. The observed LCMS (m/z) values for these examples are as follows; Example 68: 522.6; Example 69: 494.6; Example 70: 560.4. Example 71, as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 7. The observed LCMS (m/z) value for this example is 556.6. Examples 72 to 75, as shown in Table 1, were made by procedures analogous to those described above for Example 4. The observed LCMS (m/z) values for these examples are as follows; Example 72: 538.6; Example 73: 580.7; Example 74: 538.8; Example 75:
554.7. Examples 76 to 78, as shown in Table 1, were made by procedures analogous to those described above for Example 7. The observed LCMS (m/z) values for these examples are as follows; Example 76: 586.7; Example 77: 587.6; Example 78: 585.6. Examples 79 and 80, as shown in Table 1, were made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) values for these examples are as follows; Example 79: 518.7; Example 80: 492.8. Example 81, as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 7. The observed LCMS (m/z) value for this example is 506.6. Example 82, as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 9. The observed LCMS (m/z) value for this example is 508.8. Example 83:
1-Naphthalen-2-ylmethyl-3-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-ylcarbamoyl)-1H-indole-6-carboxylic acid methyl ester.
To a solution of a 3-formyl-1H-indole-6-carboxylic acid methyl ester (2.5 g) in dry DMF (50 mL) was added K2CO3 (2.5g). To this reaction mixture was added 2- (bromomethyl)-naphthalene (3.25 g) and the reaction mixture was heated to 80 ^C overnight. The mixture was then cooled to rt and ethyl acetate (50 mL) and water were added. The organic layer was separated and diluted with hexane (50 mL). The resulting solid was filtered and dried to give 3-formyl-1-naphthalen-2-ylmethyl-1H-indole-6- carboxylic acid methyl ester (3.7 g).
To a stirring solution of 3-formyl-1-naphthalen-2-ylmethyl-1H-indole-6-carboxylic acid methyl ester (3.5 g) in acetone (250 mL) was added KMnO4 (3.8 g) in 50 mL of H2O. The reaction mixture was stirred at rt for 60 min and H2O2 (10 mL) was slowly added. The resulting suspension was filtered through celite and the cake was washed with DCM (200 mL). The filtered organic layer was separated, washed with 1.0 N HCl, water, brine, dried over Na2SO4, and evaporated. The residue was dissolved in ethyl acetate (100 mL) and hexane (50 mL) and stirred at rt for 30 min. The resulting solid was filtered and the solid was further washed with 1:1 EtOAc:hexane (50 mL) and dried to afford 1-naphthalen-2- ylmethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (1.6 g).
1-Naphthalen-2-ylmethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (1.2 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give the title compound (1.1 g). LCMS (m/z): 520.8. Example 84:
6-(3,5-Dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide. 6-(3,5-Dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.35 g) was prepared according to General Procedure E using 6-bromo-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.70 g, intermedate 3) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (0.47 g).
The above ester (0.35 g) was dissolved in 1:1 THF: methanol (20 mL) and was added 2.0 N lithium hydroxide (5.0 mL). The mixture was heated at 80 ^C overnight, cooled to rt and 1.0 N HCl (5 mL) was added. The reaction mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to give 6-(3,5-dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.25g).
6-(3,5-Dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.22g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give the title compound (0.19 g). LCMS (m/z): 558.1. Example 85:
6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide.
To a stirring solution of 1H-indole-6-carboxylic acid (1.9 g) in dry DCM (10 mL) and dry THF (5.0 mL) was added 2,3,4,5,6-pentafluorophenol (2.61 g, 1.2 eq). To this reaction mixture DIC (1.78 g, 1.2 eq.) was added and stirring continued for 1.0 h. The solvent was evaporated, and the product was dried in vacuo and used for the next step without further purification. The above crude material and N-hydroxyacetamidine (1.8 g) were dissolved in toluene (50 mL) and 2.0 g of powdered 4 Ǻ molecular sieves was added. The reaction mixture was refluxed for 6.0 h, cooled, and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-20 % EtOAc in hexane to give 6-(3-methyl- [1,2,4]oxadiazol-5-yl)-1H-indole (0.45 g).
6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.27 g) was synthesized according to General Procedure B starting from 6- (3-methyl-[1,2,4]oxadiazol-5-yl)-1H-indole (0.4g).
6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.2 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give the title compound (0.11 g). LCMS (m/z): 545.2. Example 86:
6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.30 g, intermedate 3), KOAc (0.15 g) and bis(pinacolato)diboron (0.8 g) were suspended in DME (10 mL) and the mixture was purged with nitrogen for 10 min. To this solution was added 1,1′-bis[(diphenyl-phosphino)ferrocene]-dichloropalladium(II) DCM complex (65 mg, 10 mol%) and the solution was purged with nitrogen for another 10 min. The reaction mixture was stirred at 90 °C overnight, cooled to rt, and extracted with EtOAc. The organic layer was washed with water and brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatgraphy using a gradient of 0-15 % EtOAc in hexane to give 1-naphthalen-2-ylmethyl-6-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-1H-indole-3-carboxylic acid methyl ester (0.25g).
6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid methyl ester prepared according to General Procedure E using 1- naphthalen-2-ylmethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-3- carboxylic acid methyl ester (0.25g) and 2-bromo-5-methyl-[1,3,4]thiadiazole.
The above crude ester was dissolved in 1:1 THF: methanol (10 mL) and was added 2.0 N lithium hydroxide (5.0 mL). The mixture was heated at 90 ^C overnight, cooled to rt, 1.0 N HCl (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was suspended in 25 mL of EtOAC: hexane (9:1) and the resulting solid was filtered and dried to afford 6-(5-methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl- 1H-indole-3-carboxylic acid (0.12 g).
6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.12 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give the title compound (0.065 g). LCMS (m/z): 560.9. Example 87:
1-Naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)- 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.8 g, intermedate 3) and 2-tributylstannanyl-thiazole (1.14 g, 1.5 eq) were dissolved in DMF (5.0 mL) and the mixture was purged with nitrogen for 10 min. To this reaction mixture was added dichlorobis(triphenyl phosphine) palladium (II) (142 mg, 10 mol%) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 80 °C for 3.0 h, cooled to rt and EtOAc (25 mL) and saturated KF solution (20 mL) were added. The reaction mixture was stirred at rt for 30 min and filtered through celite. The filtered organic layer was separated, washed with water, brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatgraphy using a gradient of 10-20 % EtOAc in hexane to give 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H- indole-3-carboxylic acid methyl ester (0.425g).
The above ester was dissolved in 1:1 THF:methanol (20 mL) and 2.0 N lithium hydroxide (5.0 mL) was added. The mixture was heated at 90 ^C overnight, cooled to rt, 1.0 N HCl (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried (Na2SO4) and concentrated in vacuo to give 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (0.2g).
1-Naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (0.17 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give the title compound (0.12 g). LCMS (m/z): 546.0. Examples 88 and 89 as shown in Table 1, were made by procedures analogous to those described above for Example 86. The observed LCMS (m/z) values for these examples are as follows; Example 88: 573.9; Example 89: 546.0. Example 90, as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 87. The observed LCMS (m/z) value for this example is 545.8. Example 91:
6-(1-Methyl-1H-imidazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (1.0 g, intermedate 2) (0.17 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C. The residue was dissolved in DCM (5 mL) and pyridine (5 mL) and to this mixture acetic anhydride (5.0 mL) was added. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography using 1:1
EtOAc:hexane to give acetic acid (3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-[(6- bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carbonyl)-amino]-tetrahydro-pyran-2-yl ester (1.17 g).
The above compound (0.5 g) was dissolved 7.0 N NH3 in methanol (3.0 mL) and stirred at rt for 3.0 h. The solvent was evaporated and the residue was washed with 1:1 EtOAc:hexane to give 6-bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.35 g).
The above compound (0.3 g) and 1-methyl-2-tributylstannanyl-1H-imidazole (0.308 g, 1.5 eq) were dissolved in DMF (5.0 mL) and the mixture was purged with nitrogen for 10 min. To this reaction mixture was added dichlorobis(triphenylphosphine) palladium(II) (39 mg, 10 mol%) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 800C for 3.0 h, cooled to rt, and EtOAc (25 mL) and saturated KF solution (20 mL) were added. The reaction mixture was stirred at rt for 30 min and filtered through celite. The filtered organic layer was separated, washed with water , brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatgraphy using a gradient of 2-10% MeOH in DCM to give 6-(1-methyl-1H- imidazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)- 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (70 mg). LCMS (m/z): 543.0. Example 92, as shown in Table 1, was made by procedures analogous to those described above for Example 87. The observed LCMS (m/z) value for this example is 529.8. Example 93:
1-Naphthalen-2-ylmethyl-1H-indole-3,6-dicarboxylic acid 6-amide 3-[((3R,4R,5S,6R)- 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide]
To a solution of a 3-formyl-1H-indole-6-carboxylic acid methyl ester (2.5 g) in dry DMF (50 mL) was added K2CO3 (2.5 g). To this reaction mixture 2-(bromomethyl)- naphthalene (3.25 g) was added and the reaction mixture was heated to 80 ^C overnight. The mixture was then cooled to rt and ethyl acetate (50 mL) and water were added. The organic layer was separated and diluted with hexane (50 mL). The resulting solid was filtered and dried to give 3-formyl-1-naphthalen-2-ylmethyl-1H-indole-6-carboxylic acid methyl ester (3.7 g).
The above ester (2.0 g) was dissolved in 1:1 THF:methanol (30 mL) and 2.0 N lithium hydroxide (14.55 mL, 5 eq) was added. The mixture was refluxed overnight, cooled to rt, 1.0 N HCl (15 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo to give 3-formyl-1-naphthalen-2-ylmethyl-1H-indole-6-carboxylic acid (1.7g).
3-Formyl-1-naphthalen-2-ylmethyl-1H-indole-6-carboxylic acid (0.7 g) and HBTU (889 mg, 1.1 eq) were dissolved in DMF and 2.0 mL of 7.0 N ammonia in methanol was added. The reaction mixture was stirred at rt for 45 min, 2.0 N NaOH (5.0 mL) and EtOAc (15 mL) were added, and stirring continued for 1.0 h. The organic layer was separated, washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give 3-formyl- 1-naphthalen-2-ylmethyl-1H-indole-6-carboxylic acid methylamide (0.35 g).
To a stirring solution of 3-formyl-1-naphthalen-2-ylmethyl-1H-indole-6-carboxylic acid methylamide (0.35 g) in acetone (20 mL) was added 0.34 g of KMnO4 in 5.0 mL of H2O. The reaction mixture was stirred at rt for 120 min and then H2O2 (3.0 mL) was slowly added. The resulting suspension was filtered through celite and the cake was washed with EtOAc (20 mL). The filtered organic layer was separated, washed with 1.0 N HCl, water, brine, dried over Na2SO4 and evaporated to afford 6-methylcarbamoyl-1-naphthalen-2- ylmethyl-1H-indole-3-carboxylic acid (0.15 g).
6-Methylcarbamoyl-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.1 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give the title compound (0.025 g). LCMS (m/z): 505.8. Example 94:
6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
1H-Indole-6-carboxylic acid (1.0 g) was reacted with propargylamine (409 mg, 1.2 eq) according to General Procedure C (this reaction was carried out at rt) to give 1H-indole- 6-carboxylic acid prop-2-ynylamide. The crude material was used for the next step without further purification.
The above crude material and Hg(OAc)2 (1.98 g, 1.0 eq) were dissolved in AcOH (10 mL) and refluxed for 4.0 h. The solution was evaporated and the residue was dissolved in DCM (20 mL), washed with water and sat NaHCO3 solution. The organic layer was separated, dried over Na2SO4 and evaporated. The residue was purified by silica gel column chromatography using a gradient of 10-20% EtOAc in hexane to give 6-(5-methyl-oxazol- 2-yl)-1H-indole (0.65 g).
6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.15 g) was synthesized according to General Procedure B starting from 6-(5-methyl- oxazol-2-yl)-1H-indole (0.6 g).
6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.15 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give the title compound (0.070 g). LCMS (m/z): 543.9. Example 95:
6-Hydroxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide
6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.5 g) was synthesized according to General Procedure B starting from 6-benzyloxy-1-naphthalen-2- ylmethyl-1H-indole (8.7 g).
6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.4 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.10 g).
6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.090 g) was dissolved in DCM (1 mL). To this solution was added pyridine (1 mL) and then acetic anhydride (1.0 mL). The reaction mixture was concentrated and the residue was dissolved in DCM. The solution was washed with H2O, brine, dried over Na2SO4, and evaporated to afford acetic acid (3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-[(6-benzyloxy-1- naphthalen-2-ylmethyl-1H-indole-3-carbonyl)-amino]-tetrahydro-pyran-2-yl ester (0.1 g). This compound was dissolved in 4:1 EtOAc:MeOH (5 mL) and 10%Pd/C (30 mg) was added. The reaction mixture was degassed and then hydrogenated using a balloon filled with hydrogen for 90 min. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure and the product dried to afford acetic acid
(3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-[(6-hydroxy-1-naphthalen-2-ylmethyl- 1H-indole-3-carbonyl)-amino]-tetrahydro-pyran-2-yl ester (0.07 g).
Acetic acid (3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-[(6-hydroxy-1- naphthalen-2-ylmethyl-1H-indole-3-carbonyl)-amino]-tetrahydro-pyran-2-yl ester (0.02 g) was dissolved in 7.0 N NH3 in methanol (3.0 mL) and was stirred at rt for 3.0 h. The solvent was evaporated and the residue was washed with 1:1 EtOAc:hexane to give title compound (0.012 g). LCMS (m/z): 478.9. Examples 96 and 97, as shown in Table 1, were made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) values for these examples are as follows; Example 96: 506.9 and Example 97: 499.9. Example 98, as shown in Table 1, was made by procedures analogous to those described above for the compound of Example 87. The observed LCMS (m/z) value for this example is 529.8. Example 99:
1-Naphthalen-2-ylmethyl-3-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-ylcarbamoyl)-1H-indole-6-carboxylic acid
1-Naphthalen-2-ylmethyl-3-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-ylcarbamoyl)-1H-indole-6-carboxylic acid methyl ester (Example 83, 0.2 g) was dissolved in THF (3.0 mL), MeOH (3.0 mL) and 2.0 N LiOH (2.0 mL) and was stirred at rt overnight. The pH of the solution was adjusted to 6-7 by adding saturated aqueous citric acid solution. The mixture was concentrated in vacuo and the residue was suspended in DCM (5.0 mL) and MeOH (5.0 mL). The mixture was stirred for 10 min and filtered. The filtrate was concentrated under reduced pressure and the product dried to afford the title compound (0.18 g). LCMS (m/z): 506.9. Examples 100, 101 and 102, as shown in Table 1, were made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) values for these examples are as follows; Example 100: 482.9, Example 101: 532.7 and Example 102:
508.9. Examples 103 and 104, as shown in Table 1, were made by procedures analogous to those described above for Example 86. The observed LCMS (m/z) values for these examples are as follows; Example 103: 559.7 and Example 104: 560.0. Examples 105 and 106, as shown in Table 1, were made by procedures analogous to those described above for Example 1. The observed LCMS (m/z) values for these examples are as follows; Example 105: 463.6; Example 106: 462.8. Examples 107, as shown in Table 1, was made by procedures analogous to those described above for Example 86. The observed LCMS (m/z) value for this example is 545.7. Example 108:
6-Methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid {(3R,4R, 5S,6R)-6-[(2,2- dichloro-acetylamino)-methyl]-2,4,5-trihydroxy-tetrahydro-pyran-3-yl}-amide
The title compound was prepared from Example 80, 6-methoxy-1-naphthalen-2- ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-amide, following these steps:
Step 1: Example 80, 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R, 5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (4.92 g, 10.0 mmol) was dissolved in allyl alcohol (20 mL) and 2.5 mL hydrochloric acid (6.0 N solution in water) was added and the mixture was heated at 120 oC for 6 h. The mixture was allowed to cool to rt, was concentrated under reduced pressure, and the residue was purified via silica gel chromatography using 2-10% MeOH in DCM as eluent to give 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R, 5S,6R)- 2-allyloxy-4,5-dihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)–amide (4.7 g). LCMS: m/z 533.
Step 2: The intermediate from step 1, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ((3R,4R,5S,6R)-2-allyloxy-4,5-dihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-amide. (4.7 g, 8.8 mmol) was dissolved in dry pyridine (10 mL) then cooled to 0 oC. To this solution p-toulenesulfonyl chloride (2.01 g, 10.6 mmol) was added and the mixture was stirred at 0 oC for 30 min then at rt for 6 h. The mixture was then poured into saturated NaHCO3 solution (100 mL) and extracted with EtOAc (100 mL). The organic layer was concentrated under reduced pressure and the residue was purified via medium-pressure silica gel chromatography (MPLC) using 50:50 EtOAc:DCM as eluent to afford the p-toluenesulfonate intermediate (4.3 g). LCMS: m/z 687.
Step 3: The intermediate from step 2, toluene-4-sulfonic acid (2R,3S,4R,5R)-6- allyloxy-3,4-dihydroxy-5-[(6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carbonyl)- amino]-tetrahydro-pyran-2-ylmethyl ester (4.3 g, 6.25 mmol) was dissolved in dry DMF (10 mL) and treated with sodium azide (1.97 g, 31.0 mmol). The reaction mixture was heated at 80 oC for 4h. The mixture was then poured into brine (50 mL) and extracted with EtOAc (100 mL). The organic phase was separated and concentrated under reduced pressure. The residue was purified via medium pressure silica gel chromatography (MPLC) using 20:80 to 50:50 EtOAc:DCM gradient as eluent to afford the azide intermediate (2.7 g). LCMS: m/z 558.
Step 4: The intermediate from step 3, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ((3R,4R, 5S,6R)-2-allyloxy-6-azidomethyl-4,5-dihydroxy- tetrahydro-pyran-3-yl)-amide (2.23 g, 4.0 mmol) was dissolved in THF (20 mL).
Triphenylphosphine (2.62 g, 10.0 mmol) was added at rt and the reaction mixture was stirred for 10 min. Water (2.0 mL) was added and the mixture was stirred at rt for 16 h. The mixture was then concentrated under reduced pressure and the residue was purified via medium pressure silica gel chromatography (MPLC) using 2-10% MeOH in 5% ammonia- DCM as eluent to afford the amine intermediate (1.8 g). LCMS: m/z 532.
Step 5: The intermediate from step 4, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid ((3R, 4R, 5S, 6R)-2-allyloxy-6-aminomethyl-4,5-dihydroxy- tetrahydro-pyran-3-yl)-amide (106 mg, 0.2 mmol) was dissolved in EtOAc (5 mL) and treated with saturated NaHCO3 solution (5 mL). Dichloroacetyl chloride (0.1 mL, 1.0 mmol) was added and the reaction mixture was stirred at rt for 6 h. The mixture was then poured into brine (10 mL) and extracted with EtOAc (20 mL). The organic phase was concentrated in vacuo and the residue was purified via medium pressure silica gel chromatography (MPLC) using 50:50 to 90:10 EtOAc:DCM as eluent to afford the corresponding amide intermediate (72 mg). LCMS: m/z 642.
Step 6: The intermediate from step 5, 6-methoxy-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid {(3R,4R,5S,6R)-2-allyloxy-6-[(2,2-dichloro-acetylamino)- methyl]-4,5-dihydroxy-tetrahydro-pyran-3-yl}-amide (64 mg, 0.1 mmol) was dissolved in dry MeOH (2 mL) and palladium (II) chloride (18 mg, 0.1 mmol) was added. The reaction mixture was heated at 50 oC for 2h. The mixture was then passed through a pad of silica gel:celite (50:50, 10 g) and the pad was washed with DCM and MeOH. The eluent was concentrated in vacuo and the residue was purified via medium pressure silica gel chromatography (MPLC) using 5-10% MeOH in DCM as eluent to afford 6-methoxy-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid {(3R,4R, 5S,6R)-6-[(2,2-dichloro- acetylamino)-methyl]-2,4,5-trihydroxy-tetrahydro-pyran-3-yl}-amide (33 mg). LCMS: m/z 602.1H NMR (400 MHz, CD3OD): δ 7.96 (d, 1H), 7.92 (s, 1H), 7.84 (d, 2H), 7.78 (br, 1H), 7.67 (s, 1H), 7.44–7.47 (m, 2H), 7.34 (d, 1H), 6.96 (d, 1H), 6.86 (dd, 1H), 5.55 (s, 2H), 4.92 (m, 1H), 4.44 (d, 1H), 4.26–4.38 (m, 2H), 4.00–4.13 (m, 2H), 3.79 (s, 1H), 3.76 (s, 3H), 3.46 (m, 1H), 3.12 (d, 1H), and 2.68 (s, 1H) ppm (resonances for OH protons are not visible). Example 109:
2,2-Dimethyl-propionic acid (2R,3S,4R,5R)-3,4,6-trihydroxy-5-[(6-methoxy-1-naphthalen- 2-ylmethyl-1H-indole-3-carbonyl)-amino]-tetrahydro-pyran-2-ylmethyl ester
To a stirring solution of 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (Example 80) (492 mg, 1.0 mmol) in anhydrous THF (5.0 mL) was added trimethylacetyl chloride (0.123 mL, 1.0 mmol) and pyridine (0.089 mL, 1.0 mmol). The reaction was stirred at rt for 12 hr. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using 0-5% MeOH in DCM as eluent to give the title compound (79 mg). LCMS: m/z 576.9.1H NMR (400 MHz, CD3OD): δ 7.97 (d, 1H), 7.93 (s, 1H), 7.72–7.80 (m, 3H), 7.63 (br, 1H), 7.42–7.46 (m, 2H), 7.29 (d, 1H), 6.92 (d, 1H), 6.82 (dd, 1H), 5.49 (s, 2H), 5.25 and 4.74 (m, 1H), 4.22–4.40 (m, 2H), 4.00–4.13 (m, 2H), 3.84 (m, 1H), 3.73 (s, 3H), 3.46 (m, 1H), 1.22 (s, 9H) ppm (resonances for heteroatomic protons (eg. NH, OH ) are not visible). Example 110:
(3aR,5R,6S,7R,7aR)-2-[1-(3,4-Dichlorobenzyl)-6-methoxy-1H-indol-3-yl]-5- hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
Step 1: 1-(3,4-Dichlorobenzyl)-6-methoxy-1H-indole-3-carboxylic acid (2.56 g) was prepared according to General Procedure A using 6-methoxy-1H-indole-3-carboxylic acid (1.91 g) and 3,4-dichlorobenzyl chloride (2.80 mL). LCMS: m/z 349.9 Step 2: 1-(3,4-Dichlorobenzyl)-6-methoxy-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.768 g) was prepared according to General Procedure C using alpha-D-glucosamine hydrochloride (0.430 g) and 1-(3,4-dichloro-benzyl)-6-methoxy-1H-indole-3-carboxylic acid (0.700 g). LCMS: m/z 510.8.1H NMR (400 MHz, CD3OD): δ 8.07 (s, 1H), 7.67 (d, 1H), 7.48 (d, 1H), 7.37 (d, 1H), 7.30 (d, 1H), 7.13 (d, 1H), 6.87 (dd, 1H), 5.41 (s, 2H), 5.27 and 4.74 (m, 1H), 3.58– 4.09 (m, 8H), 3.41– 3.48 (m, 1H) ppm.
Step 3: Acetic acid (3R,4R,5S,6R)-2,5-diacetoxy-6-acetoxymethyl-3-{[1-(3,4- dichlorobenzyl)-6-methoxy-1H-indole-3-carbonyl]-amino}-tetrahydro-pyran-4-yl ester (591 mg) was prepared according to General Procedure D using 1-(3,4-dichlorobenzyl)-6- methoxy-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-yl)-amide (511 mg). LCMS: m/z 678.7
Step 4: Acetic acid (3aR,5R,6S,7R,7aR)-7-acetoxy-5-acetoxymethyl-2-[1-(3,4- dichlorobenzyl)-6-methoxy-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-6- yl ester (235 mg) was prepared according to General Procedure P using acetic acid
(3R,4R,5S,6R)-2,5-diacetoxy-6-acetoxymethyl-3-{[1-(3,4-dichlorobenzyl)-6-methoxy-1H- indole-3-carbonyl]-amino}-tetrahydro-pyran-4-yl ester (340 mg). LCMS: m/z 618.6.1H NMR (400 MHz, CD3OD): δ 7.99 (d, 1H), 7.89 (s, 1H), 7.46 (d, 1H), 7.38 (d, 1H), 7.09 (dd, 1H), 6.92 (d, 1H), 6.88 (dd, 1H), 6.17 (d, 1H), 5.41 (s, 2H), 5.38 (m, 1H), 4.91 (m, 1H), 4.40 (m, 1H), 4.08– 4.19 (m, 2H), 3.79 (s, 3H), 3.70 (m, 1H), 2.14 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H) ppm. Step 5: The title compound (42 mg) was prepared according to General Procedure Q using acetic acid (3aR,5R,6S,7R,7aR)-7-acetoxy-5-acetoxymethyl-2- [1-(3,4-dichlorobenzyl)-6-methoxy-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]oxazol-6-yl ester (62 mg). LCMS: m/z 492.7.1H NMR (400 MHz, CD3OD): δ 8.00 (d, 1H), 7.86 (s, 1H), 7.46 (d, 1H), 7.36 (d, 1H), 7.09 (dd, 1H), 6.89 (d, 1H), 6.86 (dd, 1H), 6.16 (d, 1H), 5.41 (s, 2H), 4.21 (m, 1H), 4.03 (m, 1H), 3.78 (s, 3H), 3.75 (m, 1H), 3.56– 3.66 (m, 2H), 3.43 (m, 1H) ppm. Example 111:
(3aR,5R,6S,7R,7aR)-2-[1-(3,4-Dichlorobenzyl)-6-methanesulfonyl-1H-indol-3-yl]-5- hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
Step1:1-(3,4-Dichlorobenzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid (140 mg) was synthesized according to General Procedure R starting from 6-methanesulfonyl- 1H-indole (250 mg). Step 2: 1-(3,4-Dichloro-benzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid (140 mg) was reacted with alpha-D-glucosamine hydrochloride (83 mg) according to the General Procedure C to give 1-(3,4-dichlorobenzyl)-6-methanesulfonyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (60 mg). LCMS: m/z 558.3
Step 3: The title compound (8 mg) was prepared according to General Procedures D, P and Q starting from 1-(3,4-dichlorobenzyl)-6-methanesulfonyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (20 mg). LCMS: m/z 540.5 Example 112:
1-[1-(3,4-Dichloro-benzyl)-3-((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-hydroxymethyl- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-2-yl)-1H-indol-6-yl]-ethanone
Step 1: Intermediate 1 (0.25 g) and 1-ethoxyvinyltripropyl-stannane (0.29 g) in DMF (5.0 mL) was purged with nitrogen (10 min). To this solution dichloro
bis(triphenylphosphine) palladium (II) (0.059 g) was added. The reaction mixture was degassed for 10 minutes and heated at 90 ^C overnight. The mixture was cooled to room temperature, EtOAc (10 ml) and 1.0 N HCl (10 ml) were added and the mixture was stirred at room temperature for 1 hour. To this mixture 20 mL of 1.0 N KF solution was added and stirred for another 30 minutes. The organic layer was separated, washed with water and brine, and dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography using DCM as eluent to give 6-acetyl-1-(3,4-dichlorobenzyl)- 1H-indole-3-carboxylic acid methyl ester (0.20 g).
Step 2: 6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in THF (5 mL) and MeOH (2.5 mL). To this stirring solution 2.0 mL of 2.0 N KOH was added and reaction the mixture stirred at 80 ^C overnight. The reaction mixture was allowed to cool to room temperature, and then 1.0 N HCl was added (pH ~ 7), and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, and dried (Na2SO4). Concentration in vacuo gave 6-acetyl-1-(3,4-dichloro-benzyl)- 1H-indole-3-carboxylic acid (0.15 g).
Step 3: 6-Acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid (89 mg) was treated with alpha-D-glucosamine hydrochloride (63 mg) according to the General
Procedure C to give 6-acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (25 mg). LCMS: m/z 522.7
Step 4: The title compound (12 mg) was prepared according to General Procedures D, P and Q starting from 6-acetyl-1-(3,4-dichloro-benzyl)-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (25 mg). LCMS: m/z 504.5 Example 113:
(3aR,5R,6S,7R,7aR)-2-[1-(3,4-Dichloro-benzyl)-6-ethoxy-1H-indol-3-yl]-5- hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
To a stirring solution of 1H-indol-6-ol (0.5 g) in DMF (5.0 mL) at -20 ^C was added NaH (0.18 g). The reaction mixture was allowed to warm to room temperature and then ethyl bromide (0.81 g) was added and stirring continued for 90 minutes. The reaction mixture was poured into ice water (10 ml) and was extracted with ethyl acetate. The organic layer was washed with water, dried (Na2SO4), concentrated in vacuo, and the residue was purified by silica gel column chromatography using 0-10% EtOAc in hexane to give 6- ethoxy-1H-indole (0.336 g).
1-(3,4-Dichloro-benzyl)-6-ethoxy-1H-indole-3-carboxylic acid (0.30 g) was synthesized according to General Procedure R starting from 6-ethoxy-1H-indole (0.33 g).
1-(3,4-Dichloro-benzyl)-6-ethoxy-1H-indole-3-carboxylic acid (0.18 g) was reacted with alpha-D-glucosamine hydrochloride (0.13 g) according to the General Procedure C to give 1-(3,4-dichloro-benzyl)-6-ethoxy-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (60 mg). LCMS: m/z 524.5 The title compound (20 mg) was prepared according to General Procedures D, P and Q starting from 1-(3,4-dichloro-benzyl)-6-ethoxy-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (50 mg). LCMS: m/z 506.5 Example 114:
1-(3,4-Dichloro-benzyl)-3-((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-hydroxymethyl-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]oxazol-2-yl)-1H-indole-6-carboxylic acid methylamide
Step 1: 1H-Indole-6-carboxylic acid (500 mg) was reacted with 2.0 M methylamine in MeOH (6.2 mL) according to the General Procedure C to give 1H-indole-6-carboxylic acid methyl amide (150 mg). Step 2: 1-(3,4-Dichloro-benzyl)-6-methylcarbamoyl-1H-indole-3-carboxylic acid (30 mg) was synthesized according to General Procedure R starting from 1H-indole-6- carboxylic acid methyl amide (150 mg).
Step 3: 1-(3,4-Dichloro-benzyl)-6-methylcarbamoyl-1H-indole-3-carboxylic acid (20 mg) was treated with alpha-D-glucosamine hydrochloride (13 mg) according to the General Procedure C to give 1-(3,4-dichloro-benzyl)-1H-indole-3,6-dicarboxylic acid 6- methylamide 3-[((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide] (18 mg). LCMS: m/z 537.5
Step 4: The title compound (5 mg) was prepared according to General Procedures D, P and Q starting with 1-(3,4-dichloro-benzyl)-1H-indole-3,6-dicarboxylic acid 6- methylamide 3-[((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide] (16 mg). LCMS: m/z 519.7 Example 115:
(3aR,5R,6S,7R,7aR)-2-[1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indol-3-yl]-5- hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
Step 1: 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was prepared according to General Procedure E using Intermediate 1 (0.20 g) and pyridine-3-boronic acid (0.19 g).
Step 2: 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid methyl ester (0.20 g) was dissolved in 1:1 THF:methanol (10 mL) and was treated with 2.5 M sodium hydroxide (3 mL). The mixture was heated at 60 ^C overnight. The solution was concentrated in vacuo and the residue was neutralized to a pH of about 4 with 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to give 1-(3,4-dichloro- benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid (150 mg). LCMS m/z: 396.8
Step 3: 1-(3,4-Dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid (90 mg) was treated with alpha D-glucosamine hydrochloride (113 mg) according to General Procedure C to give 1-(3,4-dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (75 mg) LCMS (m/z): 557.9
Step 4: The title compound (16 mg) was prepared according to General Procedures D, P and Q starting from 1-(3,4-dichloro-benzyl)-6-pyridin-3-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (35 mg). LCMS: m/z 539.7 Example 116:
(3aR,5R,6S,7R,7aR)-5-Hydroxymethyl-2-(6-methoxy-1-naphthalen-2-ylmethyl-1H-indol- 3-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
Step 1: 6-Methoxy-1H-indole-3-carboxylic acid (150 mg) was treated with 2- bromomethyl-naphthalene (207 mg) according to the General Procedure A to give 6- methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (150 mg).
Step 2: 6-Methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (50 mg) was treated with alpha-D-glucosamine hydrochloride (35 mg) according to the General Procedure C to give 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (35 mg). LCMS: m/z 492.8
Step 3: The title compound (7 mg) was prepared according to General Procedures D, P and Q starting from 6-methoxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (15 mg). LCMS: m/z 474.8 Examples 117 to 125, as shown in Table 1, were made by procedures analogous to those described above for Example 110. The observed LCMS (m/z) values for these examples are as follows; Example 117: 492.7; Example 118: 492.5; Example 119: 492.5; Example 120: 492.5; Example 121: 496.4; Example 122: 496.5; Example 123: 462.8; Example 124: 493.6; Example 125: 463.7. Examples 126 and 127, as shown in Table 1, were made by procedures analogous to those described above for Example 111. The observed LCMS (m/z) values for these examples are as follows; Example 126: 476.6; Example 127: 504.7. Examples 128 to 132, as shown in Table 1, were made by procedures analogous to those described above for Example 115. The observed LCMS (m/z) values for these examples are as follows; Example 128: 569.7; Example 129: 567.9; Example 130: 569.7; Example 131: 616.4; Example 132: 570.9. Examples 133 to 141, as shown in Table 1, were made by procedures analogous to those described above for Example 116. The observed LCMS(m/z) values for these examples are as follows; Example 133: 469; Example 134: 508.5; Example 135: 424.7; Example 136: 438.7; Example 137: 500.8; Example 138: 430.8; Example 139: 432.9; Example 140:
390.8; Example 141: 504. Example 142:
Toluene-4-sulfonic acid (3aR,5R,6S, 7R,7aR)-2-[1-(3,4-dichloro-benzyl)-6-methoxy-1H- indol-3-yl]-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-5-ylmethyl ester Toluene-4-sulfonic acid (3aR,5R,6S, 7R,7aR)-2-[1-(3,4-dichloro-benzyl)-6- methoxy-1H-indol-3-yl]-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-5- ylmethyl ester (0.53 g) was prepared from (3aR,5R,6S,7R,7aR)-2-[1-(3,4-dichloro-benzyl)- 6-methoxy-1H-indol-3-yl] -5-hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]oxazole-6,7-diol (0.49 g) and p-toluenesulfonyl chloride (0.15 g) and pyridine (0.2 ml) in DCM (10 mL). The reaction mixture was stirred at 0 ºC and allowed to warm to room temperature with stirring overnight. The mixture was poured into dilute HCl (50 ml) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography using ethyl acetate:DCM (20:80 to 50:50) as eluent to give the title compound (0.53 g). LCMS: m/z 646.6 Example 143:
(3aR,5R,6S,7R,7aR)-5-Aminomethyl-2- [1-(3,4-dichloro-benzyl)-6-methoxy-1H-indol-3- yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
(3aR,5R,6S,7R,7aR)-5-Azidomethyl-2- [1-(3,4-dichloro-benzyl)-6-methoxy-1H- indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol (0.34 g) was prepared by reacting toluene-4-sulfonic acid (3aR,5R,6S, 7R,7aR)-2-[1-(3,4-dichloro-benzyl)-6- methoxy-1H-indol-3-yl]-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-5- ylmethyl ester (0.47 g) with sodium azide (0.25 g) in DMF (5 mL) at 90 ºC overnight. The mixture was poured into water (25 mL) and extracted with ethyl acetate (2 x 50 ml). The organics were combined and washed with brine (2 x 50 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel flash column chromatography using 5% MeOH in ethyl acetate:DCM (50:50) as eluent to give the product (0.34 g).
LCMS: m/z 518.0
(3aR,5R,6S,7R,7aR)-5-Aminomethyl-2- [1-(3,4-dichloro-benzyl)-6-methoxy-1H- indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol (0.16 g) was prepared by stirring a mixture of (3aR,5R,6S,7R,7aR)-5-azidomethyl-2- [1-(3,4-dichloro-benzyl)-6- methoxy-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol (0.2 g) and triphenylphosphine (0.33 g) in THF (5 mL) and water (0.2 mL) at room temperature overnight. The reaction mixture was then concentrated and purified by silica gel flash column chromatography using MeOH-TEA-DCM (1:1:8) as eluent to give the desired product (0.16 g). LCMS: m/z 491.6 Examples 144 to 146, as shown in Table 1, were made by procedures analogous to those described above for Examples 110, 117, and 124, respectively, except that Step 5 is not performed. The observed LCMS (m/z) values for these examples are as follows: Example 144: 618.6; Example 145: 618.7; Example 146: 619.6. Example 147:
(3aR,5R,6S,7R,7aR)-5-Hydroxymethyl-2-[6-(5-methyl-[1,3,4]thiadiazol-2-yl)-1- naphthalen-2-ylmethyl-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7- diol
6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.30 g, intermedate 3), KOAc (0.15 g), and bis(pinacolato) diboron (0.8 g) were suspended in DME (10 mL) and the mixture was purged with nitrogen for 10 min. To this solution was added 1,1′-bis(diphenyl-phosphino)ferrocene]-dichloropalladium (II) DCM complex (63 mg,10 mol%) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 900C overnight, cooled to rt, and extracted with EtOAc. The organic layer was washed with water and brine and dried over Na2SO4. The solvent was evaporated in vacuo and the residue was purified by column chromatgraphy on silica gel using a gradient of 0-15 % EtOAc in hexane to give 1-naphthalen-2-ylmethyl-6-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-3-carboxylic acid methyl ester (0.25 g).
6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid methyl ester was prepared according to General Procedure E using 1- naphthalen-2-ylmethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole-3- carboxylic acid methyl ester (0.25g) and 2-bromo-5-methyl-[1,3,4]thiadiazole.
The above crude ester was dissolved in 1:1 THF:methanol (10 mL) and 2.0 N lithium hydroxide (5.0 mL) was added. The mixture was heated at 90 ^C overnight, cooled to rt, 1.0 N HCl (10 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was suspended in 25 mL of EtOAC:hexane (9:1) and the resulting solid was filtered and dried to afford 6-(5-methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H- indole-3-carboxylic acid (0.12 g).
6-(5-Methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.12 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(5-methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl- 1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-yl)-amide (0.065 g).
The title compound (25 mg) was prepared according to General Procedures D, P and Q starting from 6-(5-methyl-[1,3,4]thiadiazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide LCMS: m/z 543.0 Examples 148, as shown in Table 1, was made by procedures analogous to those described above for Example 116. The observed LCMS (m/z) value for this example is 489.0. Example 149:
3aR,5R,6S,7R,7aR)-2-[6-(3,5-Dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indol- 3-yl]-5-hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
6-(3,5-dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.35 g) was prepared according to General Procedure E using 6-bromo-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.70 g, intermedate 3) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (0.47 g).
The above ester (0.35 g) was dissolved in 1:1 THF:methanol (20 mL) and 2.0 N lithium hydroxide (5.0 mL) was added. The mixture was heated at 80 ^C overnight, cooled to rt, and 1.0 N HCl (5 mL) was added. The reaction mixture was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to give 6-(3,5- dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.25g).
6-(3,5-Dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.22g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(3,5-dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (0.19 g). The title compound (79 mg) was prepared according to General Procedures D, P and Q starting from 6-(3,5-dimethyl-isoxazol-4-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (0.10 g). LCMS (m/z): 540.0 Example 150:
(3aR,5R,6S,7R,7aR)-5-Hydroxymethyl-2-[6-(1-methyl-1H-imidazol-2-yl)-1-naphthalen-2- ylmethyl-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (1.0 g, intermedate 2) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C. The residue was dissolved in DCM (5 ml), pyridine (5 ml) and then acetic anhydride (5.0 mL) was added. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography using 1:1 EtOAc:hexane to give acetic acid (3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-[(6-bromo-1-naphthalen-2-ylmethyl-1H- indole-3-carbonyl)-amino]-tetrahydro-pyran-2-yl ester (1.17 g).
The above compound (0.5 g) was dissolved 7.0 N NH3 in methanol (3.0 mL) and stirred at rt for 3.0 h. The solvent was evaporated and the residue was washed with 1:1 EtOAc:hexane to give 6-bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.35 g).
The above compound (0.3 g) and 1-methyl-2-tributylstannanyl-1H-imidazole (0.308 mg, 1.5 eq) were dissolved in DMF (5.0 mL) and the mixture was purged with nitrogen for 10 min. To this reaction mixture was added dichlorobis(triphenyl phosphine) palladium (II) (39 mg, 10 mol%) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 80 °C for 3.0 h and cooled to rt. EtOAc (25 mL) and saturated KF solution (20 mL) were added. The reaction mixture was stirred at rt for 30 min and filtered through celite. The filtered organic layer was separated, washed with water, brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by sillica gel column chromatgraphy using a gradient of 2-10% MeOH in DCM to give 6-(1- methyl-1H-imidazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (70 mg).
The title compound (10 mg) was prepared according to General Procedures D, P and Q starting from 6-(1-methyl-1H-imidazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (20 mg). LCMS (m/z): 525.0 Example 151:
(3aR,5R,6S,7R,7aR)-5-Hydroxymethyl-2-(1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H- indol-3-yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (0.8 g, intermedate 3), and 2-tributylstannanyl-thiazole (1.14g, 1.5 eq) were dissolved in DMF (5.0 mL) and the mixture was purged with nitrogen for 10 min. To this reaction mixture was added dichlorobis(triphenyl phosphine) palladium II (142mg, 10 mol%) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 80 °C for 3.0 h, cooled to room temperature, and EtOAc (25 mL) and saturated KF solution (20 mL) were added. The reaction mixture was stirred at room temperature for 30 min and filtered through celite. The filtered organic layer was separated, washed with water , brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by sillica gel column chromatgraphy using a gradient of 10-20 % EtOAc in hexane to give 1-naphthalen- 2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid methyl ester (0.425 g).
The above ester was dissolved in 1:1 THF: methanol (20 mL) and 2.0 N lithium hydroxide (5.0 mL) was added. The mixture was heated at 90 ^C overnight, then cooled to rt, 1.0 N HCl (10 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried (Na2SO4) and concentrated in vacuo and dried to give 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (0.2 g)
1-Naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid (0.17 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 1-nnaphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)- 2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.12 g).
The title compound (12 mg) was prepared according to General Procedures D, P and Q starting from 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (20 mg). LCMS (m/z): 527.7 Examples 152, as shown in Table 1, was made by procedures analogous to those described above for Example 151. The observed LCMS (m/z) value for this example is 511.9. Example 153:
3-((3aR,5R,6S,7R,7aR)-6,7-Dihydroxy-5-hydroxymethyl-5,6,7,7a-tetrahydro-3aH- pyrano[3,2-d]oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-6-carboxylic acid methyl ester
To a solution of a 3-formyl-1H-indole-6-carboxylic acid methyl ester (2.5 g) in dry DMF (50 mL) was added K2CO3 (2.5g). To this reaction mixture 2-(bromomethyl)- naphthalene (3.25 g) was added and the reaction mixture was heated to 80 ^C overnight. The mixture is then cooled to room temperature and ethyl acetate (50 ml) and water were added. The organic layer was separated and diluted with hexane (50 mL). The resulting solid was filtered and dried to give 3-formyl-1-naphthalen-2-ylmethyl-1H-indole-6- carboxylic acid methyl ester (3.7 g)
To a stirring solution of a 3-formyl-1-naphthalen-2-ylmethyl-1H-indole-6- carboxylic acid methyl ester (3.5 g) in acetone (250 mL) was added KMnO4 (3.8 g) in 50 ml of H2O. The reaction mixture was stirred at rt for 60 min and H2O2 (10 mL) was slowly added. The resulting suspension was filtered through celite and the cake was washed with DCM (200 mL). The filtered organic layer was separated, washed with 1.0 N HCl, water, brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and hexane (50 mL) was added, stirred at rt for 30 min. The resulting solid was filtered and the solid was further washed with 1:1 EtOAc:hexane (50 mL) and dried to afford 1-naphthalen-2-ylmethyl-1H-indole-3,6-dicarboxylic acid 6- methyl ester (1.6 g).
1-Naphthalen-2-ylmethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (1.2 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 1-naphthalen-2-ylmethyl-3-((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl- tetrahydro-pyran-3-ylcarbamoyl)-1H-indole-6-carboxylic acid methyl ester (1.1 g).
The title compound (50 mg) was prepared according to General Procedures D, P and Q starting from 1-naphthalen-2-ylmethyl-3-((3R,4R,5S,6R)-2,4,5-trihydroxy-6- hydroxymethyl-tetrahydro-pyran-3-ylcarbamoyl)-1H-indole-6-carboxylic acid methyl ester (100 mg). LCMS (m/z): 502.9 Examples 154, as shown in Table 1, was made by procedures analogous to those described above for Example 116. The observed LCMS (m/z) value for this example is 517.0. Example 155:
(3aR,5R,6S,7R,7aR)-5-Hydroxymethyl-2-(6-hydroxy-1-naphthalen-2-ylmethyl-1H-indol-3- yl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.5 g) was synthesized according to the General Procedure R starting from 6-benzyloxy-1-naphthalen- 2-ylmethyl-1H-indole (8.7 g).
6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.4 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5- trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.10 g).
6-Benzyloxy-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid
((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (0.090 g) was dissolved in DCM (1 ml) and pyridine (1 ml) and then acetic anhydride (1.0 mL) was added. The reaction mixture was slowly concentrated in vacuo and the residue was dissolved in DCM, washed with H2O, brine , dried over Na2SO4 and evaporated to afford acetic acid (3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-[(6-benzyloxy-1-naphthalen-2- ylmethyl-1H-indole-3-carbonyl)-amino]-tetrahydro-pyran-2-yl ester (0.1 g). This compound was dissolved in 4:1 EtOAc:MeOH (5 mL) and 10% Pd/C (30 mg) was added. The reaction mixture was degassed and hydrogenated using a hydrogen balloon
(approximately 1 atm) for 90 min. The mixture was filtered through celite and the filtrate was concentrated to dryness in vacuo to afford acetic acid (3R,4R,5S,6R)-4,5-diacetoxy-6- acetoxymethyl-3-[(6-hydroxy-1-naphthalen-2-ylmethyl-1H-indole-3-carbonyl)-amino]- tetrahydro-pyran-2-yl ester (0.07 g).
The title compound (30 mg) was prepared according to General Procedures P and Q starting from acetic acid (3R,4R,5S,6R)-4,5-diacetoxy-6-acetoxymethyl-3-[(6-hydroxy-1- naphthalen-2-ylmethyl-1H-indole-3-carbonyl)-amino]-tetrahydro-pyran-2-yl ester (35 mg) LCMS (m/z): 460.9 Examples 156, as shown in Table 1, was made by procedures analogous to those described above for Example 151. The observed LCMS (m/z) value for this example is 528.0. Example 157:
(3aR,5R,6S,7R,7aR)-5-Hydroxymethyl-2-[6-(5-methyl-oxazol-2-yl)-1-naphthalen-2- ylmethyl-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol 1H-Indole-6-carboxylic acid (1.0 g) was reacted with propargyl amine (409 mg, 1.2 eq) according to the general procedure C (this reaction was carried out at rt) to give 1H- indole-6-carboxylic acid prop-2-ynyl amide. The crude material was used for the next step without further purification.
The above crude material and Hg(OAc)2 (1.98g, 1.0 eq) were dissolved in AcOH (10 mL) and refluxed for 4.0 h. The soution was evaporated and the residue was dissolved in DCM (20 mL) and was washed with water and saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 10-20% EtOAc in hexane to give 6-(5-methyl-oxazol-2-yl)-1H-indole (0.65 g).
6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.15 g) was synthesized according to the general procedure R starting from 6-(5-methyl- oxazol-2-yl)-1H-indole (0.6 g).
6-(5-Methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid (0.15 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(5-methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (0.070 g).
The title compound (20 mg) was prepared according to General Procedures D, P and Q starting from 6-(5-methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)-amide (35 mg). LCMS (m/z): 525.9 Example 158, as shown in Table 1, was made by procedures analogous to those described above for Example 116. The observed LCMS (m/z) value for this example is 464.9. Example 159, as shown in Table 1, was made by procedures analogous to those described above for Example 151. The observed LCMS (m/z) value for this example is 512.0. Example 160:
(3aR,5R,6S,7R,7aR)-5-Hydroxymethyl-2-[6-(3-methyl-[1,2,4]oxadiazol-5-yl)-1- naphthalen-2-ylmethyl-1H-indol-3-yl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7- diol
To a stirring solution of 1H-indole-6-carboxylic acid (1.9 g) in dry DCM (10 mL) and dry THF (5.0 mL) was added 2,3,4,5,6-pentafluorophenol (2.69 g, 1.2 eq). To this reaction mixture DIC (2.9g, 1.2 eq) was added and stirring continued for 1.0 h. The solvent was evaporated and the crude product was dried in vacuo and used for the next step without further purification.
The above crude material and N-hydroxyacetamidine (1.8 g) were dissolved in toluene (50 mL) and 2.0 g of powdered 4 Ǻ molecular sieves was added. The reaction mixture was refluxed for 6.0 h, cooled to rt, and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography using a gradient of 10-20 % EtOAc in hexane to give 6-(3-methyl-[1,2,4]oxadiazol-5-yl)- 1H-indole (0.45 g).
6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.27 g) was synthesized according to General Procedure R starting from 6- (3-methyl-[1,2,4]oxadiazol-5-yl)-1H-indole (0.4g).
6-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid (0.2 g) was reacted with alpha D-glucosamine hydrochloride according to General Procedure C to give 6-(3-methyl-[1,2,4]oxadiazol-5-yl)-1-naphthalen-2-ylmethyl- 1H-indole-3-carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro- pyran-3-yl)-amide (0.11 g).
The title compound (3.5 mg) was prepared according to General Procedures D, P and Q starting from 6-(5-methyl-oxazol-2-yl)-1-naphthalen-2-ylmethyl-1H-indole-3- carboxylic acid ((3R,4R,5S,6R)-2,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-3-yl)- amide (30 mg). LCMS (m/z): 526.9 Example 161, as shown in Table 1, was made by procedures analogous to those described above for Example 147. The observed LCMS (m/z) value for this example is 541.8. Example 162, as shown in Table 1, was made by procedures analogous to those described above for Example 116. The observed LCMS (m/z) value for this example is 482.5. Example 163, as shown in Table 1, was made by procedures analogous to those described above for Example 147. The observed LCMS (m/z) value for this example is 541.8. Examples 164 and 165, as shown in Table 1, were made by procedures analogous to those described above for Example 116. The observed LCMS (m/z) values for these examples are as follows; Example 164: 478.9; Example 165: 490.9. Example 166:
(3aR,5R,6S,7R,7aR)-2-[1-(3,4-Dichloro-benzyl)-6-methoxy-1H-indol-3-yl] -5- methylaminomethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazole-6,7-diol
The title compound was prepared by reacting toluene-4-sulfonic acid (3aR,5R,6S, 7R,7aR)-2-[1-(3,4-dichloro-benzyl)-6-methoxy-1H-indol-3-yl]-6,7-dihydroxy-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]oxazol-5-ylmethyl ester (Example 142, 63 mg, 0.1 mmol) in dioxane:THF (1:1 v/v 4 ml) with methyl amine (0.2 mL, 2M in THF) at 120 oC using microwave for 30 min. After concentration at reduced pressure, the crude material was purified by column chromatography on silica gel using 15-20% methanol in DCM to give the title compound. LCMS: m/z 505.9 [M+1]. Example 167:
N-{(3aR,5R,6S,7R,7aR)-2-[1-(3,4-Dichloro-benzyl)-6-methoxy-1H-indol-3-yl]-6,7- dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-5-ylmethyl}-acetamide
The title compound was prepared from Example 143, (3aR,5R,6S,7R,7aR)-5- aminomethyl-2- [1-(3,4-dichloro-benzyl)-6-methoxy-1H-indol-3-yl]-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]oxazole-6,7-diol (25 mg, 0.05 mmol) following these two steps.
Step 1: The starting material amine (25 mg, 0.05 mmol) and pyridine (0.05 ml) in DCM (2 ml) was cooled to 0 oC then acetic anyhdride (0.25 mmol) was added to this solution at 0 oC and stirred for 4 h. After completion of the reaction, the mixture was poured into water (10 ml) and extratcted with EtOAc (20 ml) and concentrated to give the triacetate intermediate (21 mg). This intermediate was then subjected to next step without further purification.
Step 2: The title compound was prepared according to general procedure Q using the above intermediate from step 1 (21 mg) and ammonia (0.25 ml, 7.0 N in MeOH). LCMS: m/z 533.8 [M+1].
Examples of compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof having useful biological activity are listed by name above in Table 1. The ability of compounds Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof to inhibit the activity of HK2 and inhibit the proliferation of cancer cells was established with the representative compounds of Formula (I) or Formula (II) or pharmaceutically acceptable salts thereof, and is disclosed in Tables 2, 3, and 4 using the assays described below. B. Biological Assays
The following assay methods were used to identify and evaluate compounds of Formula (I) or Formula (II) that are effective in inhibiting the HK2 enzyme.
Hexokinase 2 (HK2) Enzyme Assay
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. Typically, assays were performed by incubating enzyme (0.2– 10 nM) with or without inhibitor (0.00001-100 µM), 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 µL. 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 µL ADP-Glo and plates were incubated at room temperature for 40 minutes. Then 20 µL 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).
Measurement of ADP was accomplished by generating an ADP standard curve according to the manufacturer’s protocol. RFUs were converted to ADP concentration (µM) from the ADP standard curve. Total RFUs (C+) and background control RFUs (C-) wells contained DMSO instead of compound. A plot of ADP concentration (µM) against log compound was generated, and IC50 values were determined from plots using GraphPad PRISM according to the 4 parameter logistic equation Y=Bottom+(Top- Bottom)/1+10^((Log(IC50)-X)*HillSlope)) where X is the logarithm of compound concentration and Y is ADP concentration in µM. In Vitro Cell Proliferation Assay
Compounds were tested for their ability to inhibit cell proliferation and viability. Dual Hoechst 33342 dye/ propidium iodide staining was used to measure cell number and cell viability.
The antiproliferative activity of compounds was 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) were 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 was removed and replaced with 90 ^L fresh media. Compound (0.00001-100 µM) was diluted in media containing 3% DMSO and added to cells. Untreated cells or cells containing compound were incubated for 24-96 hours. During the last 30 minutes of the incubation period, 10 µL of a propidium iodide (10 µg/mL)/Hoescht 33342 dye reagent (32 µM) in PBS was added to each well and incubated in a humidified incubator at 37 ºC, 95% O2, 5% CO2.
Propidium iodide/ Hoechst 33342 fluorescent staining of cells was measured using an IN Cell 2000 analyzer instrument with 10X objective. The instrument setting for the Hoechst channel was excitation at 350 nm and emission at 455 nm. The setting for the propidium iodide channel was excitation at 550 nm and emission at 605 nm. The nuclei were counted in the Hoechst 33342 channel; the dead cells were counted in the propidium iodide channel. Compound IC50 values were determined from the cell number (Hoechst nuclear dye) versus compound concentration curve plots using GraphPad PRISM according to the 4 parameter logistic equation Y=Bottom+(Top-Bottom)/1+10^((Log(IC50)-X)*Hill Slope)). For cell death analysis, compound IC50 values were determined from percentage of cells positive for PI dye versus compound concentration curve plots using GraphPad PRISM according to the 4 parameter logistic equation Y=Bottom+(Top- Bottom)/1+10^((Log(IC50)-X)*Hill Slope)).
Table 2, below, shows the results for various compounds tested in the HK2 Enzyme Assay, described above. Results are reported as the concentration at which the IC50 was observed on the response curve. T 2 HK2 E A
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Table 3, below, shows the results for various compounds tested in the HK2 Enzyme Assay, described above. Results are reported as the concentration at which the IC50 was observed on the response curve. Table 3: HK2 Enzyme Assay
Figure imgf000141_0002
Table 4, below, shows the results for various compounds tested in the In Vitro Cell Proliferation Assay, described above. Results are reported as the concentration at which the IC50 was observed on the response curve. Table 4: In Vitro Cell Proliferation Assay
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

Claims: 1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000145_0001
wherein:
R1 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
(heterocyclyl)alkyl, aralkyl, or heteroaralkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, and heteroaralkyl groups are optionally substituted;
R2 represents -OH;
R3 represents -OH, -O-R31, -NH2, -NH-R31, or NR31R32;
R4 represents -OH, -O-R41, -NH2, -NH-R41, or NR41R42;
R5 represents -G5-OH, -G5-O-R51, -G5-NH2, -G5-NH-R51, or -G5-NR51R52;
G5 represents -CRaRb-,-C(O)-, or a bond;
Z represents O, NH, NRZ1, or NC(O)RZ1;
X1 represents N or C-R7;
R6 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(O)-R61, -C(O)-OR61, -C(O)-NR61, -C(S)-R61,-C(S)-NR61, or -SO2-R61, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R7 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R71, -SH, -S- R71, -S(O)R71, -SO2-R71, -NH2, -NH-R71, -NR71R72, -C(O)-R71, -CO2H, -C(O)-O- R71, -O-C(O)-R71, -O-C(O)-OR71, -C(O)-NH2, -C(O)-NH-R71, -C(O)-NR71R72, -NH- C(O)-R71, -N(R72)-C(O)-R71, -NH-C(O)-NH2, -NH-C(O)-NHR71, -NH-C(O)- NR71R72, -N(R72)-C(O)-NH2, -N(R72)-C(O)-NHR71, -N(R72)-C(O)-NR71R72, -O- C(O)-NR71R72, -O-C(O)-NH-R71, -O-C(O)-NH2, -NH-C(O)-OR71, -N(R72)-C(O)- OR71, -SO2-NH2, -SO2-NH-R71, -SO2-NR71R72, -NH-SO 2
2-R71, -N(R7 )-SO2-R71, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R8a and R8b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R81, -SH, -S-R81, -S(O)R81, -SO2-R81, -NH2, -NH-R81, - NR81R82, -C(O)-R81, -CO2H, -C(O)-O-R81, -O-C(O)-R81, -C(O)-NH2, -C(O)-NH- R81, -C(O)-NR81R82, -NH-C(O)-R81, -N(R82)-C(O)-R81, -NH-C(O)-NH2, -NH-C(O)- NHR81, -NH-C(O)-NR81R82, -N(R82)-C(O)-NH2, -N(R82)-C(O)-NHR81, -N(R82)- C(O)-NR81R82, -O-C(O)-NR81R82, -O-C(O)-NH-R81, -O-C(O)-NH2, -NH-C(O)- OR81, -N(R82)-C(O)-OR81, -SO2-NH2, -SO2-NH-R81, -SO2-NR81R82, -NH-SO2-R81, -N(R82)-SO2-R81, -C(S)-NH2, -C(S)-NH-R81, -C(S)-NR81R82, -NH-C(S)-R81, - N(R82)-C(S)-R81, -NH-C(S)-NH2, -NH-C(S)-NHR81, -NH-C(S)-NR81R82, -N(R82)- C(S)-NH2, -N(R82)-C(S)-NHR81, -N(R82)-C(S)-NR81R82, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R9a and R9b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R91, -SH, -S-R91, -S(O)R91, -SO2-R91, -NH2, -NH-R91, - NR91R92, -C(O)-R91, -CO2H, -C(O)-O-R91, -O-C(O)-R91, -C(O)-NH2, -C(O)-NH- R91, -C(O)-NR91R92, -NH-C(O)-R91, -N(R92)-C(O)-R91, -NH-C(O)-NH2, -NH-C(O)- NHR91, -NH-C(O)-NR91R92, -N(R92)-C(O)-NH2, -N(R92)-C(O)-NHR91, -N(R92)- C(O)-NR91R92, -O-C(O)-NR91R92, -O-C(O)-NH-R91, -O-C(O)-NH2, -NH-C(O)- OR91, -N(R92)-C(O)-OR91, -SO2-NH2, -SO2-NH-R91, -SO2-NR91R92, -NH-SO2-R91, - N(R92)-SO2-R91, -C(S)-NH2, -C(S)-NH-R91, -C(S)-NR91R92, -NH-C(S)-R91, -N(R92)- C(S)-R91, -NH-C(S)-NH2, -NH-C(S)-NHR91, -NH-C(S)-NR91R92, -N(R92)-C(S)- NH2, -N(R92)-C(S)-NHR91, -N(R92)-C(S)-NR91R92, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,
(heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; R61, R71, R72, R81, R82, R91, and R92 are each independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
or R71 and R72, R81 and R82, or R91 and R92, 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;
R31, R32, R41, R42, R51, and R52 are each independently selected from alkyl, alkenyl,
alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, -C(O)-R103, -C(O)-O-R103, - C(O)-N(H)-R103, -C(O)-NR103R104, and -SO2-R103, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and aralkyl groups are optionally substituted; and R103 and R104 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
or R103 and R104, 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;
Ra and Rb are each independently selected from H, alkyl, (cycloalkyl)alkyl, aralkyl,
heteroaralkyl, alkenyl, and alkynyl; and
RZ1 represents alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, haloalkyl, alkoxy, or haloalkoxy. 2. The compound of claim 1, wherein R5 represents -G5-OH or -G5-O-R51.
3. The compound of any preceding claim, wherein G5 represents -CH2-.
4. The compound of claim 3, wherein R5 represents -CH2OH.
5. The compound of claim 1, wherein R5 represents -G5-NH2, -G5-NH-R51, or -G5- NR51R52.
6. The compound of claim 1 or claim 5, wherein G5 represents -CH2-.
7. The compound of claim 6, wherein R5 represents -CH2NH-R51 or -CH2NR51R52, wherein R51 is selected from -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)-R103, -C(O)-NR103R104,
Figure imgf000147_0001
8. The compound of any preceding claim, wherein R1 represents H or alkyl.
9. The compound of any preceding claim, wherein R1 represents H.
10. The compound of any preceding claim, wherein Z represents O or NH.
11. The compound of any preceding claim, wherein Z represents O.
12. The compound of any preceding claim, wherein R3 and R4 are both -OH.
13. The compound of any preceding claim, wherein X1 represents N or CH.
14. The compound of any preceding claim, wherein X1 represents CH.
15. The compound of any preceding claim, wherein R6 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,
(heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
16. The compound of any preceding claim, wherein R6 represents substituted or unsubstituted (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl.
17. The compound of any preceding claim, wherein R6 represents substituted or unsubstituted -CH2-(1-naphthyl), -CH2-(2-naphthyl), or -CH2-(phenyl).
18. The compound of claim 17, wherein R6 represents -CH2-(1-naphthyl), -CH2-(2- naphthyl), or -CH2-(phenyl), substituted at any position by one or more substituents R65; wherein:
R65, independently for each occurrence, is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2- R101, -NH2, -NH-R101, -NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, -C(O)-NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -O-C(O)-OR101, -NH-C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, - N(R102)-C(O)-NH2, -N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)- NR101R102, -O-C(O)-NH-R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)- OR101, -SO2-NH2, -SO2-NH-R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2- R101, halogen, -NO2, and cyano; and R101 and R102 independently for each occurrence represent substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
19. The compound of claim 18, wherein R65 is selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
20. The compound of any preceding claim, wherein R8a and R8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR81, halogen, and cyano.
21. The compound of any preceding claim, wherein R8a and R8b are each hydrogen.
22. The compound of any preceding claim, wherein R9a and R9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR91, halogen, and cyano.
23. The compound of any preceding claim, wherein at least one of R9a and R9b represents -OR91.
24. The compound of claim 23, wherein R9b represents -OR91.
25. The compound of claim 23 or claim 24, wherein R91 represents alkyl.
26. A compound of Formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000149_0001
(II)
wherein:
R3 represents -OH, -O-R31, -NH2, -NH-R31, or NR31R32;
R4 represents -OH, -O-R41, -NH2, -NH-R41, or NR41R42;
R5 represents -G5-OH, -G5-O-R51, -G5-NH2, -G5-NH-R51, or -G5-NR51R52;
G5 represents -CRaRb-, -C(O)-, or a bond;
Z represents O, NH, NRZ1, or NC(O)RZ1;
X1 represents N or C-R7;
R6 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(O)-R61, -C(O)-OR61, -C(O)-NR61, -C(S)-R61, -C(S)-NR61, or -SO2-R61, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R7 represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R71, -SH, -S- R71, -S(O)R71, -SO2-R71, -NH2, -NH-R71, -NR71R72, -C(O)-R71, -CO2H, -C(O)-O- R71, -O-C(O)-R71, -O-C(O)-OR71, -C(O)-NH2, -C(O)-NH-R71, -C(O)-NR71R72, -NH- C(O)-R71, -N(R72)-C(O)-R71, -NH-C(O)-NH2, -NH-C(O)-NHR71, -NH-C(O)- NR71R72, -N(R72)-C(O)-NH2, -N(R72)-C(O)-NHR71, -N(R72)-C(O)-NR71R72, -O- C(O)-NR71R72, -O-C(O)-NH-R71, -O-C(O)-NH2, -NH-C(O)-OR71, -N(R72)-C(O)- OR71, -SO2-NH2, -SO2-NH-R71, -SO2-NR71R72, -NH-SO2-R71, -N(R72)-SO2-R71, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R8a and R8b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R81, -SH, -S-R81, -S(O)R81, -SO2-R81, -NH2, -NH-R81, - NR81R82, -C(O)-R81, -CO2H, -C(O)-O-R81, -O-C(O)-R81, -C(O)-NH2, -C(O)-NH- R81, -C(O)-NR81R82, -NH-C(O)-R81, -N(R82)-C(O)-R81, -NH-C(O)-NH2, -NH-C(O)- NHR81, -NH-C(O)-NR81R82, -N(R82)-C(O)-NH2, -N(R82)-C(O)-NHR81, -N(R82)- C(O)-NR81R82, -O-C(O)-NR81R82, -O-C(O)-NH-R81, -O-C(O)-NH2, -NH-C(O)- OR81, -N(R82)-C(O)-OR81, -SO2-NH2, -SO2-NH-R81, -SO2-NR81R82, -NH-SO2-R81, - N(R82)-SO2-R81, -C(S)-NH2, -C(S)-NH-R81, -C(S)-NR81R82, -NH-C(S)-R81, -N(R82)- C(S)-R81, -NH-C(S)-NH2, -NH-C(S)-NHR81, -NH-C(S)-NR81R82, -N(R82)-C(S)- NH2, -N(R82)-C(S)-NHR81, -N(R82)-C(S)-NR81R82, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,
(heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R9a and R9b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R91, -SH, -S-R91, -S(O)R91, -SO2-R91, -NH2, -NH-R91, - NR91R92, -C(O)-R91, -CO2H, -C(O)-O-R91, -O-C(O)-R91, -C(O)-NH2, -C(O)-NH- R91, -C(O)-NR91R92, -NH-C(O)-R91, -N(R92)-C(O)-R91, -NH-C(O)-NH2, -NH-C(O)- NHR91, -NH-C(O)-NR91R92, -N(R92)-C(O)-NH2, -N(R92)-C(O)-NHR91, -N(R92)- C(O)-NR91R92, -O-C(O)-NR91R92, -O-C(O)-NH-R91, -O-C(O)-NH2, -NH-C(O)- OR91, -N(R92)-C(O)-OR91, -SO2-NH2, -SO2-NH-R91, -SO2-NR91R92, -NH-SO2-R91, - N(R92)-SO2-R91, -C(S)-NH2, -C(S)-NH-R91, -C(S)-NR91R92, -NH-C(S)-R91, -N(R92)- C(S)-R91, -NH-C(S)-NH2, -NH-C(S)-NHR91, -NH-C(S)-NR91R92, -N(R92)-C(S)- NH2, -N(R92)-C(S)-NHR91, -N(R92)-C(S)-NR91R92, halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,
(heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;
R61, R71, R72, R81, R82, R91, and R92 are each independently selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
or R71 and R72, R81 and R82, or R91 and R92, 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;
R31, R32, R41, R42, R51, and R52 are each independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, -C(O)-R103, -C(O)-O-R103, -C(O)-N(H)- R103, -C(O)-NR103R104, and -SO2-R103, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and aralkyl groups are optionally substituted;
R103 and R104 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or (cycloalkyl)alkyl;
or R103 and R104, 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;
Ra and Rb are each independently selected from H, alkyl, (cycloalkyl)alkyl, aralkyl,
heteroaralkyl, alkenyl, and alkynyl; and
RZ1 represents alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, haloalkyl, alkoxy, or haloalkoxy;
wherein at least one of R6, R8a, R8b, R9a, and R9b is not hydrogen.
27. The compound of claim 26, wherein Z represents O or NH.
28. The compound of claim 26 or claim 27, wherein Z represents O.
29. The compound of any one of claims 26-28, wherein X1 represents N or CH.
30. The compound of any one of claims 26-29, wherein X1 represents CH.
31. The compound of any one of claims 26-30, wherein R3 represents -OH or -O-R31, and R4 represents -OH or -O-R41.
32. The compound of any one of claims 26-31, wherein R3 represents -O-R31 and R4 represents -O-R41, wherein R31 and R41 are each independently selected from alkyl, -C(O)- R103, and -SO2-R103.
33. The compound of any one of claims 26-31, wherein R3 and R4 both represent -OH.
34. The compound of any one of claims 26-33, wherein G5 represents -CRaRb-.
35. The compound of any one of claims 26-34, wherein G5 represents -CH2-.
36. The compound of any one of claims 26-35, wherein R5 represents -G5-OH or -G5-O- R51.
37. The compound of any one of claims 26-36, wherein R5 represents -G5-OH.
38. The compound of any one of claims 26-37, wherein R5 represents -G5-O-R51, and R51 represents alkyl, -C(O)-R103, and -SO2-R103.
39. The compound of any one of claims 26-35, wherein R5 represents -G5-NH2 or -G5- NH-R51.
40. The compound of any one of claims 26-35 and 39, wherein R5 represents -G5-NH2.
41. The compound of any one of claims 26-35 and 39, wherein R5 represents -G5-NH- R51, and R51 represents alkyl, -C(O)-R103, and -SO2-R103.
42. The compound of any one of claims 26-41, wherein R6 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,
(heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
43. The compound of any one of claims 26-42, wherein R6 represents substituted or unsubstituted (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl.
44. The compound of any one of claims 26-43, wherein R6 represents (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl, substituted at any position by one or more substituents R65;
wherein:
R65, independently for each occurrence, is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R101, -SH, -S-R101, -S(O)R101, -SO2- R101, -NH2, -NH-R101, -NR101R102, -C(O)-R101, -CO2H, -C(O)-O-R101, -O-C(O)-R101, -C(O)-NH2, -C(O)-NH-R101, -C(O)-NR101R102, -NH-C(O)-R101, -N(R102)-C(O)-R101, -O-C(O)-OR101, -NH-C(O)-NH2, -NH-C(O)-NHR101, -NH-C(O)-NR101R102, - N(R102)-C(O)-NH2, -N(R102)-C(O)-NHR21, -N(R102)-C(O)-NR101R102, -O-C(O)- NR101R102, -O-C(O)-NH-R101, -O-C(O)-NH2, -NH-C(O)-OR101, -N(R102)-C(O)- OR101, -SO2-NH2, -SO2-NH-R101, -SO2-NR101R102, -NH-SO2-R101, -N(R102)-SO2- R101, halogen, -NO2, and cyano; and
R101 and R102 independently for each occurrence represent substituted or unsubstituted
alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
45. The compound of claim 44, wherein R65 is selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.
46. The compound of any one of claims 26-45, wherein R8a and R8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR81, halogen, and cyano.
47. The compound of any one of claims 26-46, wherein R8a and R8b are each hydrogen.
48. The compound of any one of claims 26-47, wherein R9a and R9b are each
independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OH, -OR91, -NH2, -NH-R91, -NR91R92, -C(O)-R91, -CO2H, -C(O)-O-R91, C(O)-NH2, -C(O)-NH-R91, -C(O)-NR91R92, -SO2-R91, -SO2-NH2, -SO2-NH-R91, -SO2- NR91R92, halogen, and cyano, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted .
49. The compound of any one of claims 26-48, wherein at least one of R9a and R9b represents -OR91.
50. The compound of claim 49, wherein R91 represents alkyl.
51. A pharmaceutical composition comprising a compound of any preceding claim and a pharmaceutically acceptable carrier.
52. A method of treating cancer, comprising administering to a subject a compound of any preceding claim.
53. The method of claim 52, wherein the cancer is a solid tumor.
54. The method of claim 53, wherein the solid tumor is a highly glycolytic tumor.
55. The method of any one of claims 52-54, wherein the subject is a mammal.
56. The method of claim 55, wherein the subject is a human.
57. The method of any one of claims 52-56, further comprising conjointly administering to the patient one or more additional chemotherapeutic agents.
58. The method of claim 57, wherein conjointly administering one or more additional chemotherapeutic agents provide improved efficacy relative to each individual
administration of the compound of any one of claims 1-50 or the one or more additional chemotherapeutic agents.
59. The method of claim 58, wherein conjointly administering one or more additional chemotherapeutic agents provides a synergistic effect.
60. The method of claim 58, wherein conjointly administering one or more additional chemotherapeutic agents provides an additive effect.
61. The method of any of claims 57-60, wherein the compound of any one of claims 1- 50 and the one or more additional chemotherapeutic agents are administered
simultaneously.
62. The method of any of claims 57-60, wherein 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 compound of any one of claims 1-49.
63. The method of any of claims 57-62, wherein the one or more additional
chemotherapeutic agents are selected from aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bisphosphonate, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol, 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, vinblastine, vincristine, vindesine, and vinorelbine.
64. The method of any one of claims 57-62, wherein the one or more additional chemotherapeutic agents are selected from 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.
65. The method of any one of claims 57-62, wherein the one or more additional chemotherapeutic agents is an immune-oncology therapeutic, such as an inhibitor of arginase, CTLA-4, indoleamine 2,3-dioxygenase, and PD-1/PD-L1.
66. A method inhibiting proliferation of a cancerous cell comprising contacting a cancerous cell with an effective amount of a compound of any one of claims 1-50.
67. A method of inhibiting hexokinase activity in a cell, comprising contacting a cell with a compound of any one of claims 1-50.
68. The method of claim 67, wherein the cell is a cancer cell.
69. The method of claim 67 or claim 68, wherein the contacting occurs in vitro.
70. The method of claim 67 or claim 68, wherein the contacting occurs in vivo.
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