WO2016176636A1 - Inhibiteurs de transport de créatine et leurs utilisations - Google Patents

Inhibiteurs de transport de créatine et leurs utilisations Download PDF

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WO2016176636A1
WO2016176636A1 PCT/US2016/030243 US2016030243W WO2016176636A1 WO 2016176636 A1 WO2016176636 A1 WO 2016176636A1 US 2016030243 W US2016030243 W US 2016030243W WO 2016176636 A1 WO2016176636 A1 WO 2016176636A1
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acid
amino
cancer
pyridin
carboxylic acid
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Eduardo J. Martinez
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Inspirna Inc
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Rgenix Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/34—Isothioureas having sulfur atoms of isothiourea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/46—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/18—Nitrogen atoms not forming part of a nitro radical with hetero atoms attached to said nitrogen atoms, except nitro radicals, e.g. hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • Creatine is synthesized in the liver and kidney and transported throughout the body to tissues with high energy demands through an active transport system. Creatine is used by the body during times of increased energy demands to rapidly resynthesize ATP from ADP through the anaerobic conversion of phosphorylated creatine (phosphocreatine) to creatine in a reversible reaction by the enzyme creatine kinase. In times of low energy demands, excess ATP can be utilized to convert creatine to phosphocreatine. Increased expression of creatine kinase promotes metastasis by enhancing the survival of disseminated cancer cells in the liver where they encounter hepatic hypoxia.
  • Increased expression of creatine kinase results in production of excess phosphocreatine which may be used as an energetic store for generating ATP needed to endure hepatic hypoxia. Inhibition of the phosphocreatine system through inhibition of creatine uptake and/or creatine kinase in cancer cells is thus a therapeutic target for the treatment of cancer and/or metastasis.
  • This invention features compounds that inhibit creatine transport and/or creatine kinase, pharmaceutical compositions including the compounds of the invention, and methods of utilizing those compositions for inhibition of creatine transport and/or creatine kinase (e.g. , for the treatment of cancer).
  • the invention features a compound having the structure of Formula I :
  • X 1 is absent, NH, or CH2;
  • R 1 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl ;
  • R 2 , R 3 , and R 4 are independently hydrogen or optionally substituted C1 -C6 alkyl ;
  • R 5 and R 6 are hydrogen or NH2
  • R 5 and R 6 are both hydrogen or R 5 is NH2 and R 6 is hydrogen then R 2 is optionally substituted C1 -C6 alkyl ,
  • R 1 is hydrogen. In other embodiments, R 3 and R 4 are hydrogen. In certain embodiments, R 2 is hydrogen or optionally substituted C1 -C6 alkyl (e.g. , methyl , ethyl, isopropyl, propyl , isobutyl , or optionally substituted C1 -C6 haloalkyl such as, trifluoromethyl.
  • C1 -C6 alkyl e.g. , methyl , ethyl, isopropyl, propyl , isobutyl , or optionally substituted C1 -C6 haloalkyl such as, trifluoromethyl.
  • R 5 and R 6 are both hydrogen and R 2 is optionally substituted C1 -C6 alkyl (e.g. , methyl , ethyl , isopropyl , or isobutyl).
  • C1 -C6 alkyl e.g. , methyl , ethyl , isopropyl , or isobutyl.
  • R 5 and R 6 are both NH2.
  • R 2 is hydrogen.
  • R 2 is optionally substituted C1 -C6 alkyl (e.g. , methyl or isopropyl) .
  • R 5 is NH2
  • R 6 is hydrogen
  • R 2 is optionally substituted C1 -C6 alkyl (e.g., methyl or isopropyl).
  • R 5 is hydrogen and R 6 is NH2.
  • R 2 is hydrogen.
  • R 2 is optionally substituted C1 -C6 alkyl (e.g., methyl or isopropyl).
  • X 1 is absent. In some embodiments, X 1 is CH2. In other embodiments, X 1 is NH 2 .
  • the compound is a compound of Table 1 (e.g., compound 225, 229, 230, 234, or 235).
  • the compound is a compound of Table 3 (e.g., compound 250 or 251 ).
  • Table 3 Selected Phosphocreatine System Inhibitors
  • the invention features a compound having the structure of Formula II:
  • Q 1 is optionally substituted amidino or optionally substituted 2-pyridyl
  • X 2 is S or NR 12 ;
  • n 0 or 1 ;
  • R 7 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl;
  • R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH2, optionally substituted C1 -C6 alkyl, or R 8 or R 9 can combine with R 10 or R 1 1 to form an optionally substituted C3-C6 cycloalkyi ring or with R 12 to form an optionally substituted C3-C6 heterocycle;
  • R 10 and R 1 1 are independently hydrogen, deuterium, optionally substituted C1 -C6 alkyl, or R 10 or R 1 1 can combine with R 8 or R 9 to form an optionally substituted C3-C6 cycloalkyi ring;
  • R 12 is hydrogen, optionally substituted C1 -C6 alkyl, or R 12 can combine with R 8 or R 9 to form an optionally substituted C3-C6 heterocycle, and
  • R 9 is halo then R 8 is halo or optionally substituted C1 -C6 alkyl
  • R 12 is hydrogen
  • R 7 is hydrogen. In other embodiments, m is 1 . In certain embodiments, R 9 is hydrogen, deuterium, or halo (e.g., fluoro). In some embodiments, R 1 1 is hydrogen or deuterium.
  • R 8 and R 10 combine to form an optionally substituted C3-C6 cycloalkyi ring
  • R 10 and R 1 1 are deuterium. In other embodiments,
  • R 8 and R 9 are deuterium. In some embodiments, both R 8 and R 9 are halo (e.g., fluoro). In other embodiments, R 10 is optionally substituted C1 -C6 alkyl (e.g., optionally substituted C1 -C6 haloalkyl such as, trifluoromethyl).
  • R 8 is NH2.
  • R 10 is optionally substituted C1 -C6 alkyl (e.g., methyl).
  • Q 1 is optionally substituted amidino (e.g., ⁇ 2 ).
  • X 2 is NR 12 .
  • R 8 and R 12 combine to form an optionally substituted C3- C6 heterocycle (e.g., azetidine).
  • R 12 is hydrogen.
  • X 2 is S.
  • Q 1 is optionally substituted 2-pyridyl (e.g., ).
  • X 2 is NR 12 and R 12 is hydrogen.
  • Q 1 is optionally substituted amidino or optionally substituted 2-pyridyl
  • X 2 is S or NR 12 ;
  • n 1 or 2;
  • R 7 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl;
  • R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH2, optionally substituted C1 -C3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyi ring; or R 8 or R 9 combine with R 10 or R 1 1 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyi ring; or R 8 or R 9 combine with R 12 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle;
  • R 10 and R 1 1 are independently hydrogen, deuterium, optionally substituted C1 -C4 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or R 10 and R 1 1 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyi ring; or R 10 or R 1 1 combine with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyi ring; or R 10 or R 1 1 combine with R 12 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle;
  • R 12 is hydrogen, optionally substituted C1 -C6 alkyl, or R 12 combines with R 8 , R 9 , R 10 , or R 1 1 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle,
  • R 10 and R 1 1 are independently deuterium, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or R 10 and R 1 1 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyi ring; or R 10 or R 1 1 combine with R 9 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyi ring; or R 10 or R 1 1 combine with R 12 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle; wherein if Q 1 is optionally substituted 2-pyridyl and R 10 is optionally substituted C1 -C4 alkyl then at least one of R 8 and R 9 are independently deuterium ,
  • R 8 is hydrogen, fluoro, hydroxyl , or methyl then at least one of R 9 , R 10 , and R 1 1 is not hydrogen ;
  • R 8 is NH2 and R 10 is hydrogen, methyl , or -CH2CH2OH then at least one of R 9 or R 1 1 is not hydrogen ;
  • R 12 is hydrogen
  • the invention features a compound having the structure of Formula V:
  • Q 1 is optionally substituted amidino or optionally substituted 2-pyridyl ;
  • n 1 or 2;
  • R 7 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl ;
  • R 8 and R 9 are independently hydrogen, deuterium , halo, hydroxyl, NH2, optionally substituted C1 -C3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyi ring ; or R 8 or R 9 combine with R 10 or R 1 1 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyi ring ; or R 8 or R 9 combine with R 12 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle;
  • R 10 and R 1 1 are independently hydrogen , deuterium , optionally substituted C1 -C4 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or R 10 and R 1 1 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyi ring ; or R 10 or R 1 1 combine with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyi ring ; or R 10 or R 1 1 combine with R 12 with the atoms to which they are attached to form an optionally substituted C3-C4 heterocycle;
  • R 12 is hydrogen , optionally substituted C1 -C6 alkyl , or R 12 combines with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle, or R 12 combines with R 10 or R 1 1 with the atoms to which they are attached to form an optionally substituted C3-C4 heterocycle
  • R 8 is hydrogen, halo, hydroxyl, or methyl then at least one of R 9 , R 10 , and R 1 1 is not hydrogen ;
  • R 8 is NH2 and R 10 is hydrogen, methyl , or -CH2CH2OH then at least one of R 9 or R 1 1 is not hydrogen ; wherein if m is 1 , R 8 is halo, and R 10 is optionally substituted C1 -C4 alkyl then at least one of R 9 and R 10 is not hydrogen;
  • R 7 is hydrogen.
  • Q 1 is optionally substituted amidino NH
  • Q 1 is 3 ⁇ 4 2 .
  • Q 1 is optionally substituted 2-pyridyl (e.g., 2-pyridyl).
  • R 8 combines with R 10 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyl ring.
  • the compound has the structure of Formula VI:
  • a is 0 or 1 .
  • the compound has the structure of Formula VII
  • R 9 is hydrogen, hydroxyl, or NH2. In other embodiments, R 1 1 is hydrogen.
  • m is 1 and R 10 is deuterium, optionally substituted C1 -C4 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or R 10 and R 1 1 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyl ring.
  • R 9 is hydrogen, NH2, or methyl.
  • R 10 and R 1 1 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyl ring (e.g., an optionally substituted C3-C4 cycloalkyl ring such as cyclopropyl or cyclobutyl).
  • R 8 and R 9 are both hydrogen.
  • R 8 is halo, optionally substituted C1 -C3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyl ring.
  • R 8 is halo (e.g., fluoro).
  • R 9 is halo (e.g., fluoro).
  • R 8 is optionally substituted C1 -C3 alkyl (e.g., methyl).
  • R 9 is optionally substituted C1 -C3 alkyl (e.g., methyl).
  • R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyl ring (e.g., an optionally substituted C3-C4 cycloalkyl ring such as cyclopropyl or cyclobutyl).
  • R 10 and R 1 1 are both hydrogen.
  • R 12 is hydrogen. In some embodiments, R 12 combines with R 8 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle (e.g., an optionally substituted C4-C5 heterocycle).
  • b and c are each, independently, 0 or 1 .
  • R 10 is hydrogen or optionally substituted C1 -C4 alkyl (e.g., methyl).
  • R 1 1 is hydrogen.
  • R 9 is hydrogen, halo (e.g., fluoro), hydroxyl, NH2, optionally substituted C1 -C3 alkyl (e.g., methyl).
  • R 12 combines with R 10 with the atoms to which they are attached to form an optionally substituted C3-C4 heterocycle.
  • R 1 1 is hydrogen. In other embodiments, R 8 and R 9 are both hydrogen.
  • Q 1 is 2 .
  • the compound of Formula II or Formula V is any one of compounds 253-262 or 327-385 in Table 4.
  • the compound of Formula II or Formula V is any one of compounds 263-274 or 386-436 in Table 5.
  • the invention features a compound selected from any one of compounds 253-262 and 327-385 in Table 4.
  • the compound is any one of compounds 258, 327-338, 340, 343-348, 351 -352, 366-367, 369-370, 372-375, and 379-385 in Table 4.
  • the invention features a compound selected from any one of compounds 263-274 and 386-436 in Table 5.
  • the invention features a compound selected from any one of compounds 275-286 in Table 6.
  • Table 6 Selected Phosphocreatine System Inhibitors
  • the invention features a compound of Table 7 that is substantially enantiomerically re.
  • the invention features a compound having the structure:
  • A is a inhibitor of creatine transport and/or creatine kinase comprising an amidino group
  • B has the structure:
  • n 0 or 1 ;
  • Q 2 is hydroxyl, optionally substituted amino, or -SO2OH
  • B has the structure:
  • A has the structure of any of the foregoing compounds.
  • the invention features a compound selected from any one of compounds 1 -218 26 in Table 8.
  • the invention features a compound selected from any one of compounds 287-298 in Table 9.
  • the invention features a compound selected from any one of compounds .
  • the invention features a composition comprising any of the foregoing compounds and a pharmaceutically acceptable excipient.
  • the composition is a pharmaceutical composition.
  • the creatine transport inhibitor or creatine kinase inhibitor in the composition is substantially enantiomerically pure.
  • the invention features a method for treating cancer (e.g., gastrointestinal cancer such as, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer, anal cancer, mucosa-associated lymphoid tissue cancer, gastrointestinal stromal tumors, cancers of the biliary tree, and gastrointestinal carcioid tumor), comprising administering to a subject in need thereof, any of the foregoing compounds in an amount sufficient to treat said cancer.
  • the compound is any of the foregoing compounds of Formula I, Formula II, or Formula III.
  • the compound is any compound of any one of Tables 1 -1 1 (e.g., a compound of any one of Tables 1 -7, 9 or 10).
  • the invention features a method of slowing the spread of a migrating cancer, including administering to a subject in need thereof, an inhibitor of creatine transport and/or creatine kinase in an amount sufficient to slow the spread of said migrating cancer.
  • the method comprises the suppression of metastatic colonization of said migrating cancer in the liver of said subject.
  • the migrating cancer is metastatic cancer (e.g., including cells exhibiting migration, invasion of migrating cells, endothelial recruitment, and/or angiogenesis).
  • the migrating cancer spreads via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces.
  • the migrating cancer spreads via the lymphatic system. In some embodiments, the migrating cancer spreads hematogenously. In other embodiments, the migrating cancer is a cell migration cancer (e.g., a non-metastatic cell migration cancer such as, ovarian cancer, mesothelioma, or primary lung cancer).
  • a cell migration cancer e.g., a non-metastatic cell migration cancer such as, ovarian cancer, mesothelioma, or primary lung cancer.
  • the invention features a method for inhibiting proliferation or growth of cancer stem cells or cancer initiating cells, including contacting the cell with an inhibitor of creatine transport and/or creatine kinase in an amount sufficient to inhibit proliferation or growth of said cell.
  • the invention features a method of reducing the rate of tumor seeding of a cancer including administering to a subject in need thereof an inhibitor of creatine transport and/or creatine kinase in an amount sufficient to reduce tumor seeding.
  • the invention features a method of reducing or treating metastatic nodule-forming of cancer including administering to a subject in need thereof an inhibitor of creatine transport and/or creatine kinase in an amount sufficient to treat said metastatic nodule-forming of cancer.
  • the invention features a method of treating metastatic cancer in a subject in need thereof.
  • the method includes: (a) providing a subject identified to have, or to be at risk of having, metastatic cancer on the basis of the expression level of miR-483-5p and/or miR-551 a is below a predetermined reference value or the expression level of CKB and/or SLC6a8 is above a predetermined reference value; and (b) administering to said subject an effective amount of any of the foregoing compounds.
  • the invention features a method for treating metastatic cancer in a subject in need thereof, comprising contacting creatine transport channel SLC6a8 with any of the foregoing compounds in an amount effective to suppress metastatic colonization of said cancer.
  • the cancer is breast cancer, colon cancer, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, or melanoma.
  • the cancer is gastrointestinal cancer such as, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer, anal cancer, mucosa- associated lymphoid tissue cancer, gastrointestinal stromal tumors, cancers of the biliary tree, and gastrointestinal carcioid tumor.
  • the method includes administration of any of the foregoing compositions. In some embodiments of any of the foregoing methods, the method includes administration of a composition including a creatine transport inhibitor or creatine kinase inhibitor that is substantially enantiomerically pure. In other embodiments of any of the foregoing methods, the cancer is a drug resistant cancer (e.g., the cancer is resistant to vemurafenib, dacarbazine, a CTLA4 inhibitor, a BRAF inhibitor, a MEK inhibitor, a PD1 inhibitor, or a PDL1 inhibitor).
  • the cancer is a drug resistant cancer (e.g., the cancer is resistant to vemurafenib, dacarbazine, a CTLA4 inhibitor, a BRAF inhibitor, a MEK inhibitor, a PD1 inhibitor, or a PDL1 inhibitor).
  • the method further includes administering an antiproliferative (e.g., capecitabine, gemcitabine, fluorouracil, FOLFOX (5-FU, leucovorin, and Eloxatin), FOLFIRI (5-FU, leucovorin, and Camptosar), EOX (Epirubicin, Oxaliplatinum, and Xeloda), Taxotere, Erbitux, Zaltrap, Vectibix, Ramucirumab, Tivozanib, Stivarga, CRS-207, a PD-1 or PDL-1 antibody (e.g., nivolumab, pembrolizumab, MEDI4736, or MPDL3280A), and therapies that target CDK4/6, EGFR, PARP), wherein any of the foregoing compounds and the antiproliferative are administered in an amount that together, is sufficient to slow the progression of migrating cancer.
  • an antiproliferative e.g., capecitabine,
  • the inhibitor of creatine transport and/or creatine kinase is any of the foregoing compounds of Formula I, Formula II, Formula III, or Formula V.
  • the compound is any compound of any one of Tables 1 -1 1 or a pharmaceutically acceptable salt thereof (e.g., a compound of any one of Tables 1 -7, 9 or 1 0).
  • the compound is any compound of Table 4 or a pharmaceutically acceptable salt thereof.
  • the inhibitor of creatine transport and/or creatine kinase is any one of compounds 7-9, 1 1 , 15, 16, 28, 29, 30, 32, 33, 34, 43, 47, 48, 51 , 52, 54, 67, 69, 70, 79, 80, 85, 124, 132, 149, 150, 1 87, 188, 190, 1 92-195, 1 99, 210-213, 215, 217, 324, 447, or 448 or a pharmaceutically acceptable salt thereof.
  • the inhibitor of creatine transport and/or creatine kinase is any one of compounds 16, 28, 29, 33, 34, 43, 47, 85, 124, 149, 150, 210-213, 215, 21 7, 324, 447, or 448 or a pharmaceutically acceptable salt thereof.
  • the inhibitor of creatine transport and/or creatine kinase is any one of compounds 26, 28, 34, 92, 96, 124, 125, 149, 150, 1 61 , 163, 207, 324, 447 or 448 or a pharmaceutically acceptable salt thereof.
  • the inhibitor of creatine transport and/or creatine kinase is any one of compounds 28, 34, 124, 149, or 1 50 or a pharmaceutically acceptable salt thereof. In some embodiments of any of the foregoing methods, the inhibitor of creatine transport and/or creatine kinase is compound 34, a stereoisomer thereof, and/or a pharmaceutically acceptable salt thereof. In some embodiments of any of the foregoing methods, the inhibitor of creatine transport and/or creatine kinase is any one of compounds 219-224, or a pharmaceutically acceptable salt thereof.
  • the term "compound,” is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole,
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds.
  • “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei.
  • isotopes of hydrogen include tritium and deuterium.
  • the compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges.
  • C1-6 alkyi is specifically intended to individually disclose methyl, ethyl, C3 alkyi, C4 alkyi, C5 alkyi, and Ce alkyI.
  • optionally substituted X e.g., optionally substituted alkyi
  • X optionally substituted
  • alkyi wherein the alkyi is optionally substituted
  • acyl represents a hydrogen or an alkyi group (e.g., a haloalkyl group), as defined herein, that is attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl.
  • Exemplary unsubstituted acyl groups include from 1 to 7, from 1 to 1 1 , or from 1 to 21 carbons.
  • the alkyi group is further substituted with 1 , 2, 3, or 4 substituents as described herein.
  • Non-limiting examples of optionally substituted acyl groups include, alkoxycarbonyl,
  • alkoxycarbonylacyl arylalkoxycarbonyl, aryloyl, carbamoyl, carboxyaldehyde, (heterocyclyl) imino, and
  • alkoxycarbonyl represents an alkoxy, as defined herein, attached to the parent molecular group through a carbonyl atom (e.g., -C(0)-OR, where R is H or an optionally substituted C1-6, C1-10, or C1 -20 alkyi group).
  • exemplary unsubstituted alkoxycarbonyl include from 1 to 21 carbons (e.g., from 1 to 1 1 or from 1 to 7 carbons).
  • the alkoxy group is further substituted with 1 , 2, 3, or 4 substituents as described herein.
  • alkoxycarbonylacyl represents an acyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -C(O) -alkyl-C(0)-OR, where R is an optionally substituted C1-6, C1-10, or C1-20 alkyi group).
  • Exemplary unsubstituted alkoxycarbonylacyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21 , or from 3 to 31 carbons, such as Ci-6 alkoxycarbonyl-Ci-6 acyl, C1-10 alkoxycarbonyl-Ci-10 acyl, or C1-20 alkoxycarbonyl-Ci-20 acyl).
  • each alkoxy and alkyl group is further independently substituted with 1 , 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group) for each group.
  • arylalkoxycarbonyl which as used herein, represents an arylalkoxy group, as defined herein, attached to the parent molecular group through a carbonyl (e.g., -C(O)-O-alkyl-aryl).
  • exemplary unsubstituted arylalkoxy groups include from 8 to 31 carbons (e.g., from 8 to 17 or from 8 to 21 carbons, such as C6-10 aryl-Ci-6 alkoxy-carbonyl, Ce- ⁇ aryl-Ci-10 alkoxy-carbonyl, or Ce- ⁇ aryl-Ci-20 alkoxy-carbonyl).
  • the arylalkoxycarbonyl group can be substituted with 1 , 2, 3, or 4 substituents as defined herein.
  • aryloyl which as used herein, represents an aryl group, as defined herein, that is attached to the parent molecular group through a carbonyl group.
  • exemplary unsubstituted aryloyl groups are of 7 to 1 1 carbons.
  • the aryl group can be substituted with 1 , 2, 3, or 4 substituents as defined herein.
  • R N1 is found in the definition of "amino" provided herein.
  • carboxyaldehyde which as used herein, represents an acyl group having the structure -
  • heterocyclyl imino represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an imino group.
  • the heterocyclyl group can be substituted with 1 , 2, 3, or 4 substituent groups as defined herein.
  • heterocyclyl represents a heterocyclyl group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • the heterocyclyl group can be substituted with 1 , 2, 3, or 4 substituent groups as defined herein.
  • alkyl is inclusive of both straight chain and branched chain saturated groups from 1 to 20 carbons (e.g., from 1 to 10 or from 1 to 6), unless otherwise specified.
  • Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, and neopentyl, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1 ) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2, where R N1 is as defined for amino); (4) Ce- ⁇ aryl-Ci-6 alkoxy;
  • NR N1 (CH2)s2(CH2CH 2 0)si (CH2)s3NR N1 , wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted C1 -6 alkyl; (15) -C(0)NR B' R c' , where each of R B' and R c' is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) Ce- ⁇ aryl, and (d) C1-6 alk-Ce- ⁇ aryl; (1 6) -SC R 0' , where R D' is selected from the group consisting of (a) C1-6 alkyl, (b) Ce- ⁇ aryl, (c) C
  • each R N1 is, independently, hydrogen or optionally substituted C1-6 alkyl; (19) -NR H' C(0)R r , wherein R H' is selected from the group consisting of (a1 ) hydrogen and (b1 ) C1-6 alkyl, and R r is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) Ce- ⁇ aryl, (d2) hydrogen, (e2) C1-6 alk-Ce- ⁇ aryl, (f2) amino-Ci-20 alkyl, (g2) polyethylene glycol of -(CH2)s2(OCH2CH2)si (CH2)s30R', wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently
  • alkylene and the prefix "alk-,” as used herein, represent a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, and isopropylene.
  • Cx- y alkylene and the prefix “Cx-y alk-” represent alkylene groups having between x and y carbons. Exemplary values for x are 1 , 2, 3, 4,
  • 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-6, C1-10, C2-20, C2-6, C2-10, or C2-20 alkylene).
  • the alkylene can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for an alkyl group.
  • Non-limiting examples of optionally substituted alkyl and alkylene groups include acylaminoalkyl, acyloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkylsulfinyl, alkylsulfinylalkyl, aminoalkyl, carbamoylalkyl, carboxyalkyl, carboxyaminoalkyl, haloalkyl, hydroxyalkyl, perfluoroalkyl, and sulfoalkyl:
  • acylaminoalkyl represents an acyl group, as defined herein, attached to an amino group that is in turn attached to the parent molecular group through an alkylene group, as defined herein (i.e., -alkyl-N(R N1 )-C(0)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group (e.g., haloalkyl) and R N1 is as defined herein).
  • alkylene group as defined herein (i.e., -alkyl-N(R N1 )-C(0)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group (e.g., haloalkyl) and R N1 is as defined herein).
  • Exemplary unsubstituted acylaminoalkyl groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21 , from 2 to 7, from 2 to 13, from 2 to 21 , or from 2 to 41 carbons).
  • the alkylene group is further substituted with 1 , 2, 3, or 4 substituents as described herein, and/or the amino group is -NH2 or -NHR N1 , wherein R N1 is,
  • each R N2 can be H, alkyl, or aryl.
  • acyloxyalkyl represents an acyl group, as defined herein, attached to an oxygen atom that in turn is attached to the parent molecular group though an alkylene group (i.e., -alkyl-0-C(0)-R, where R is H or an optionally substituted C1-6, C1-10, or C1 -20 alkyl group).
  • alkylene group i.e., -alkyl-0-C(0)-R, where R is H or an optionally substituted C1-6, C1-10, or C1 -20 alkyl group.
  • exemplary unsubstituted acyloxyalkyl groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 1 1 carbons).
  • the alkylene group is, independently, further substituted with 1 , 2, 3, or 4 substituents as described herein.
  • alkoxyalkyl represents an alkyl group that is substituted with an alkoxy group.
  • exemplary unsubstituted alkoxyalkyl groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C1-6 alkoxy-Ci-6 alkyl, C1 -10 alkoxy-Ci-10 alkyl, or C1-20 alkoxy-Ci-20 alkyl).
  • the alkyl and the alkoxy each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective group.
  • alkoxycarbonylalkyl represents an alkyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkyl-C(0)-OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group).
  • Exemplary unsubstituted alkoxycarbonylalkyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21 , or from 3 to 31 carbons, such as C1-6 alkoxycarbonyl-Ci-6 alkyl, C1-10 alkoxycarbonyl-Ci-10 alkyl, or C1-20 alkoxycarbonyl-Ci-20 alkyl).
  • each alkyl and alkoxy group is further independently substituted with 1 , 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).
  • alkylsulfinylalkyl represents an alkyl group, as defined herein, substituted with an alkylsulfinyl group.
  • exemplary unsubstituted alkylsulfinylalkyl groups are from 2 to 12, from 2 to 20, or from 2 to 40 carbons.
  • each alkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein.
  • aminoalkyl represents an alkyl group, as defined herein, substituted with an amino group, as defined herein.
  • the alkyl and amino each can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for the respective group (e.g., C02R A' , where R A' is selected from the group consisting of (a) C1-6 alkyl, (b) Ce- ⁇ aryl, (c) hydrogen, and (d) C1-6 alk-Ce- ⁇ aryl, e.g., carboxy, and/or an /V-protecting group).
  • the "carbamoylalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with a carbamoyl group, as defined herein.
  • the alkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein.
  • the "carboxyalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with a carboxy group, as defined herein.
  • the alkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein, and the carboxy group can be optionally substituted with one or more O-protecting groups.
  • the "carboxyaminoalkyl” group which as used herein, represents an aminoalkyl group, as defined herein, substituted with a carboxy, as defined herein.
  • the carboxy, alkyl, and amino each can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for the respective group (e.g., C02R A' , where R A' is selected from the group consisting of (a) C1-6 alkyl, (b) Ce- ⁇ aryl, (c) hydrogen, and (d) C1-6 alk- Ce-10 aryl, e.g., carboxy, and/or an /V-protecting group, and/or an O-protecting group).
  • haloalkyl represents an alkyl group, as defined herein, substituted with a halogen group (i.e., F, CI, Br, or I).
  • a haloalkyl may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens.
  • Haloalkyl groups include perfluoroalkyls (e.g., -CF 3 ), -CHF2, -CH 2 F, -CCI 3 , -CH 2 CH 2 Br, -CH2CH(CH2CH 2 Br)CH 3 , and -CHICH3.
  • the haloalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • hydroxyalkyl group which as used herein, represents an alkyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by hydroxymethyl and
  • the hydroxyalkyl group can be substituted with 1 , 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • perfluoroalkyl which as used herein, represents an alkyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical.
  • Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl.
  • the "sulfoalkyl” group which as used herein, represents an alkyl group, as defined herein, substituted with a sulfo group of -SO3H.
  • the alkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein, and the sulfo group can be further substituted with one or more O-protecting groups (e.g., as described herein).
  • alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1 -propenyl, 2-propenyl, 2-methyl-1 - propenyl, 1 -butenyl, and 2-butenyl.
  • Alkenyls include both cis and trans isomers.
  • Alkenyl groups may be optionally substituted with 1 , 2, 3, or 4 substituent groups that are selected, independently, from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • Non-limiting examples of optionally substituted alkenyl groups include, alkoxycarbonylalkenyl, aminoalkenyl, and hydroxyalkenyl :
  • alkoxycarbonylalkenyl represents an alkenyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkenyl-C(0)-OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group).
  • Exemplary unsubstituted alkoxycarbonylalkenyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21 , or from 4 to 31 carbons, such as C1 -6 alkoxycarbonyl-C2-6 alkenyl, C1-10 alkoxycarbonyl-C2-io alkenyl, or C1-20 alkoxycarbonyl- C2-20 alkenyl).
  • each alkyl, alkenyl, and alkoxy group is further independently substituted with 1 , 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).
  • aminoalkenyl represents an alkenyl group, as defined herein, substituted with an amino group, as defined herein.
  • the alkenyl and amino each can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for the respective group (e.g., C02R , where R A' is selected from the group consisting of (a) C1-6 alkyl, (b) Ce- ⁇ aryl, (c) hydrogen, and (d) C1-6 alk-Ce- ⁇ aryl, e.g., carboxy, and/or an /V-protecting group).
  • hydroxyalkenyl represents an alkenyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by dihydroxypropenyl, and hydroxyisopentenyl.
  • the hydroxyalkenyl group can be substituted with 1 , 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • alkynyl represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, and 1 -propynyl.
  • Alkynyl groups may be optionally substituted with 1 , 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • Non-limiting examples of optionally substituted alkynyl groups include alkoxycarbonylalkynyl, aminoalkynyl, and hydroxyalkynyl :
  • alkoxycarbonylalkynyl represents an alkynyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkynyl-C(0)-OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group).
  • Exemplary unsubstituted alkoxycarbonylalkynyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21 , or from 4 to 31 carbons, such as C1 -6 alkoxycarbonyl-C2-6 alkynyl, C1-10 alkoxycarbonyl-C2-io alkynyl, or C1-20 alkoxycarbonyl- C2-20 alkynyl).
  • each alkyl, alkynyl, and alkoxy group is further independently substituted with 1 , 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).
  • aminoalkynyl represents an alkynyl group, as defined herein, substituted with an amino group, as defined herein.
  • the alkynyl and amino each can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for the respective group (e.g., C02R , where R A' is selected from the group consisting of (a) C1-6 alkyl, (b) Ce- ⁇ aryl, (c) hydrogen, and (d) C1-6 alk-Ce- ⁇ aryl, e.g., carboxy, and/or an /V-protecting group).
  • hydroxyalkynyl which as used herein, represents an alkynyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group.
  • the hydroxyalkynyl group can be substituted with 1 , 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • each R N1 is, independently, H, OH, N0 2 , N(R N2 ) 2 , S0 2 OR N2 , S0 2 R N2 , SOR N2 , an /V-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyi, alkcycloalkyi, carboxyalkyi (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein),
  • Non-limiting examples of optionally substituted amidino groups include guanidino, 2-amino-imidazoyl, 2- iminoimidazolidino, 2-imino-1 ,3-diazinan-1 -yl, 3-amino-1 ,2,4-triazol-4-yl, imidazol-2yl, 1 ,4,5,6- tetrahydropyrimidin-2-yl, 1 ,2,4-triazol-3-yl, 5-amino-3,4-dihydro-pyrrol-5-yl, imidazol-1 -yl,
  • carbamimidoylsulfanyl carbamoylamino, carbamothioylamino, 2-amino-1 ,3-benzothiazol-2-yl, 2-amino-1 ,3- thiazol-2-yl, 2-amino-1 ,3-benzodiazol-2-yl, and 2-aminopyridyl.
  • amino represents -N(R N1 ) 2 , wherein each R N1 is, independently, H, OH,
  • amino groups of the invention can be an unsubstituted amino (i.e., -NH 2 ) or a substituted amino (i.e., -N(R N1 ) 2 ).
  • amino is -NH 2 or -NHR N1 , wherein R N1 is, independently, OH, N0 2 , NH 2 , NR N2 2 , S0 2 OR N2 , S0 2 R N2 , SOR N2 , alkyl, carboxyalkyi, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, and each R N2 can be H, C1-20 alkyl (e.g., C1-6 alkyl), or Ce- ⁇ aryl.
  • Non-limiting examples of optionally substituted amino groups include acylamino and carbamyl:
  • the "acylamino" group which as used herein, represents an acyl group, as defined herein, attached to the parent molecular group though an amino group, as defined herein (i.e., -N(R N1 )-C(0)-R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group (e.g., haloalkyl) and R N1 is as defined herein).
  • Exemplary unsubstituted acylamino groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21 , from 2 to 7, from 2 to 13, from 2 to 21 , or from 2 to 41 carbons).
  • the alkyl group is further substituted with 1 , 2, 3, or 4 substituents as described herein, and/or the amino group is - NH 2 or -NHR N1 , wherein R N1 is, independently, OH, N0 2 , NH 2 , NR N2 2 , S0 2 OR N2 , S0 2 R N2 , SOR N2 , alkyl, aryl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), or alkoxycarbonylalkyl, and each R N2 can be H, alkyl, or aryl.
  • R N1 is, independently, OH, N0 2 , NH 2 , NR N
  • amino acid refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of -CO2H or a sulfo group of -SO3H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain).
  • the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group.
  • Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl.
  • Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.
  • Amino acid groups may be optionally substituted with one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents independently selected from the group consisting of: (1 ) C1-6 alkoxy; (2) C1-6 alkylsulfinyl ; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH2) or a substituted amino (i.e., -N(R N1 )2, where R N1 is as defined for amino); (4) Ce- ⁇ aryl-Ci-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (1 1 ) C1-7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -C02R A' , where R A' is
  • s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R' is H or C1-20 alkyl, and (h) amino-polyethylene glycol of -
  • NR N1 (CH2)s2(CH2CH 2 0)si (CH2)s3NR N1 , wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted C1 -6 alkyl; (19) - NR H' C(0)R r , wherein R H' is selected from the group consisting of (a1 ) hydrogen and (b1 ) C1-6 alkyl, and R r is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) Ce-10 aryl, (d2) hydrogen, (e2) C1-6 alk-
  • (CH2)s2(OCH2CH2)si (CH2)s30R' wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R' is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of -
  • NR N 1 (CH2)s2(CH2CH 2 0)si (CH2)s3NR N1 wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted C1 -6 alkyl; and (21 ) amidine. In some embodiments, each of these groups can be further substituted as described herein.
  • aryl represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4- tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, and indenyl, and may be optionally substituted with 1 , 2, 3, 4, or 5 substituents independently selected from the group consisting of: (1 ) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-Ci-6 alkyl, C1-6 alkylsu If inyl-Ci -e alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl, (carboxyaldehy
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and
  • arylalkyl group which as used herein, represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alk-Ce- ⁇ aryl, C1-10 alk-Ce-10 aryl, or C1-20 alk-Ce- ⁇ aryl).
  • the alkylene and the aryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective groups.
  • Other groups preceded by the prefix "alk-" are defined in the same manner, where “alk” refers to a C1-6 alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.
  • bicyclic refers to a structure having two rings, which may be aromatic or non-aromatic.
  • Bicyclic structures include spirocyclyl groups, as defined herein, and two rings that share one or more bridges, where such bridges can include one atom or a chain including two, three, or more atoms.
  • Exemplary bicyclic groups include a bicyclic carbocyclyl group, where the first and second rings are carbocyclyl groups, as defined herein; a bicyclic aryl groups, where the first and second rings are aryl groups, as defined herein; bicyclic heterocyclyl groups, where the first ring is a heterocyclyl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group; and bicyclic heteroaryl groups, where the first ring is a heteroaryl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group.
  • the bicyclic group can be substituted with 1 , 2, 3, or 4 substituents as defined herein for cycloalkyl, heterocyclyl, and aryl groups.
  • boranyl represents -B(R B1 )3, where each R B1 is, independently, selected from the group consisting of H and optionally substituted alkyl.
  • the boranyl group can be substituted with 1 , 2, 3, or 4 substituents as defined herein for alkyl.
  • Carbocyclic and “carbocyclyl,” as used herein, refer to an optionally substituted C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms.
  • Carbocyclic structures include cycloalkyl, cycloalkenyl, and aryl groups.
  • carbonyl represents a C(O) group, which can also be represented as
  • cyano represents an -CN group.
  • cycloalkyl represents a monovalent saturated or unsaturated non- aromatic cyclic hydrocarbon group from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicycle heptyl.
  • cycloalkyl group includes one carbon-carbon double bond
  • the cycloalkyl group can be referred to as a "cycloalkenyl” group.
  • Exemplary cycloalkenyl groups include cyclopentenyl, and cyclohexenyl.
  • the cycloalkyl groups of this invention can be optionally substituted with: (1 ) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-Ci-6 alkyl, C1-6 alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl, (carboxyaldehyde)-Ci -6 alkyl, halo-Ci-6 alkyl (e.g., perfluoroalkyl), hydroxy-Ci-6 alkyl, nitro-Ci -6 alkyl, or Ci-6 thioalkoxy-Ci-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5) C6-10 aryl; (6) amino; (7) C1-6
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • cycloalkylalkyl represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein (e.g., an alkylene group of from 1 to 4, from 1 to 6, from 1 to 10, or form 1 to 20 carbons).
  • alkylene group as defined herein (e.g., an alkylene group of from 1 to 4, from 1 to 6, from 1 to 10, or form 1 to 20 carbons).
  • the alkylene and the cycloalkyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective group.
  • diastereomer as used herein means stereoisomers that are not mirror images of one another and are non-superimposable on one another.
  • enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • halo represents a halogen selected from bromine, chlorine, iodine, or fluorine.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroalkenyl and heteroalkynyl refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl and heteroalkynyl groups can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • Non-limiting examples of optionally substituted heteroalkyl, heteroalkenyl, and heteroalkynyl groups include acyloxy, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonylalkoxy, alkynyloxy, aminoalkoxy, arylalkoxy, carboxyalkoxy, cycloalkoxy, haloalkoxy, (heterocyclyl)oxy, perfluoroalkoxy, thioalkoxy, and
  • acyloxy represents an acyl group, as defined herein, attached to the parent molecular group though an oxygen atom (i.e., -0-C(0)-R, where R is H or an optionally substituted C1-6, C1-10, or C1 -20 alkyl group).
  • oxygen atom i.e., -0-C(0)-R, where R is H or an optionally substituted C1-6, C1-10, or C1 -20 alkyl group.
  • exemplary unsubstituted acyloxy groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 1 1 carbons).
  • the alkyl group is further substituted with 1 , 2, 3, or 4 substituents as described herein.
  • alkenyloxy represents a chemical substituent of formula -OR, where R is a C2-20 alkenyl group (e.g., C2-6 or C2-10 alkenyl), unless otherwise specified.
  • alkenyloxy groups include ethenyloxy, and propenyloxy.
  • the alkenyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).
  • alkoxy group which as used herein, represents a chemical substituent of formula -OR, where R is a C1-20 alkyl group (e.g., C1-6 or C1-10 alkyl), unless otherwise specified.
  • exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy.
  • the alkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein (e.g., hydroxy or alkoxy).
  • alkoxyalkoxy represents an alkoxy group that is substituted with an alkoxy group.
  • exemplary unsubstituted alkoxyalkoxy groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C1-6 alkoxy-Ci-6 alkoxy, C1-10 alkoxy-Ci-10 alkoxy, or C1-20 alkoxy-Ci-20 alkoxy).
  • the each alkoxy group can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein.
  • alkoxycarbonylalkoxy represents an alkoxy group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -0-alkyl-C(0)-OR, where R is an optionally substituted C1-6, C1-10, or C1-20 alkyl group).
  • Exemplary unsubstituted alkoxycarbonylalkoxy include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21 , or from 3 to 31 carbons, such as C1 -6 alkoxycarbonyl-Ci e alkoxy, C1-10 alkoxycarbonyl-Ci-10 alkoxy, or C1-20 alkoxycarbonyl- C1-20 alkoxy).
  • each alkoxy group is further independently substituted with 1 , 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group).
  • alkynyloxy represents a chemical substituent of formula -OR, where R is a C2-20 alkynyl group (e.g., C2-6 or C2-10 alkynyl), unless otherwise specified.
  • exemplary alkynyloxy groups include ethynyloxy, and propynyloxy.
  • the alkynyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).
  • aminoalkoxy group which as used herein, represents an alkoxy group, as defined herein, substituted with an amino group, as defined herein.
  • the alkyl and amino each can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for the respective group (e.g., C02R A , where R A' is selected from the group consisting of (a) C1-6 alkyl, (b) Ce- ⁇ aryl, (c) hydrogen, and (d) C1-6 alk-Ce- ⁇ aryl, e.g., carboxy).
  • arylalkoxy represents an alkaryl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • exemplary unsubstituted arylalkoxy groups include from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ce- ⁇ aryl-Ci-6 alkoxy, Ce- ⁇ aryl-Ci-10 alkoxy, or Ce- ⁇ aryl-Ci-20 alkoxy).
  • the arylalkoxy group can be substituted with 1 , 2, 3, or 4 substituents as defined herein.
  • aryloxy group which as used herein, represents a chemical substituent of formula -OR', where R' is an aryl group of 6 to 18 carbons, unless otherwise specified.
  • the aryl group can be substituted with 1 , 2, 3, or 4 substituents as defined herein.
  • the "carboxyalkoxy” group which as used herein, represents an alkoxy group, as defined herein, substituted with a carboxy group, as defined herein.
  • the alkoxy group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for the alkyl group, and the carboxy group can be optionally substituted with one or more O-protecting groups.
  • the "cycloalkoxy” group which as used herein, represents a chemical substituent of formula -OR, where R is a C3-8 cycloalkyl group, as defined herein, unless otherwise specified.
  • the cycloalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein. Exemplary unsubstituted cycloalkoxy groups are from 3 to 8 carbons.
  • the cycloalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein.
  • haloalkoxy which as used herein, represents an alkoxy group, as defined herein, substituted with a halogen group (i.e., F, CI , Br, or I).
  • a haloalkoxy may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens.
  • Haloalkoxy groups include
  • haloalkoxys e.g., -OCF3, -OCHF2, -OCH2F, -OCCI3, -OCH 2 CH 2 Br, -OCH2CH(CH2CH 2 Br)CH 3 , and - OCHICH3.
  • the haloalkoxy group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heterocyclyloxy represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • the heterocyclyl group can be substituted with 1 , 2, 3, or 4 substituent groups as defined herein.
  • perfluoroalkoxy which as used herein, represents an alkoxy group, as defined herein, where each hydrogen radical bound to the alkoxy group has been replaced by a fluoride radical.
  • Perfluoroalkoxy groups are exemplified by trifluoromethoxy and pentafluoroethoxy.
  • alkylsulfinyl represents an alkyl group attached to the parent molecular group through an -S(O)- group.
  • exemplary unsubstituted alkylsulfinyl groups are from 1 to 6, from 1 to 10, or from 1 to 20 carbons.
  • the alkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein.
  • thioarylalkyl which as used herein, represents a chemical substituent of formula -SR, where R is an arylalkyl group.
  • the arylalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein.
  • the "thioalkoxy” group as used herein represents a chemical substituent of formula -SR, where R is an alkyl group, as defined herein.
  • R is an alkyl group, as defined herein.
  • the alkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein.
  • the "thioheterocyclylalkyl” group which as used herein, represents a chemical substituent of formula -SR, where R is an heterocyclylalkyi group.
  • R is an heterocyclylalkyi group.
  • the heterocyclylalkyi group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein.
  • heteroaryl represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system.
  • Exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 1 1 , 1 to 10, 1 to 9, 2 to 12, 2 to 1 1 , 2 to 10, or 2 to 9) carbons.
  • the heteroaryl is substituted with 1 , 2, 3, or 4 substituents groups as defined for a heterocyclyl group.
  • heteroarylalkyl refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted heteroarylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alk-Ci-12 heteroaryl, C1-10 alk-Ci-12 heteroaryl, or C1-20 alk-Ci-12 heteroaryl).
  • the alkylene and the heteroaryl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective group.
  • HeteroarylalkyI groups are a subset of heterocyclylalkyl groups.
  • heterocyclyl represents a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds.
  • heterocyclyl groups are of 1 to 12 (e.g., 1 to 1 1 , 1 to 1 0, 1 to 9, 2 to 12, 2 to 1 1 , 2 to 10, or 2 to 9) carbons.
  • heterocyclyl also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group.
  • heterocyclyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, and benzothienyl.
  • fused heterocyclyls include tropanes and 1 ,2,3,5,8,8a- hexahydroindolizine.
  • Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquino
  • heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1 -/-imidazolyl ; 2,3,4,5-tetrahydro-5-oxo-1 H- pyrazolyl (e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1 /-/-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1 H- imidazolyl (e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1 /-/-imidazolyl) ; 2,3-dihydro-2-thioxo- 1 ,3,4-oxadiazoly
  • heterocyclics include 3, 3a, 4, 5, 6,6a- hexahydro-pyrrolo[3,4-b]pyrrol-(2 -/)-yl, and 2,5-diazabicyclo[2.2.1 ]heptan-2-yl, homopiperazinyl (or diazepanyl), tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, and thiocanyl.
  • Heterocyclic groups also include groups of the formula , where
  • E' is selected from the group consisting of -N- and -CH-;
  • F' is selected from the group consisting of -
  • any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1 ) C1-7 acyl (e.g., carboxyaldehyde ); (2) C1 -20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-Ci-6 alkyl, C1-6 alkylsulfinyl-Ci-6 alkyl, amino-Ci-6 alkyl, azido-Ci-6 alkyl,
  • heterocyclyl)imino (28) C2-20 alkenyl; and (29) C2-20 alkynyl.
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci- alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and
  • heterocyclylalkyl which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein.
  • exemplary unsubstituted heterocyclylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alk-Ci-12 heterocyclyl, C1-10 alk-Ci-12 heterocyclyl, or C1-20 alk-Ci-12 heterocyclyl).
  • the alkylene and the heterocyclyl each can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein for the respective group.
  • the term "hydrocarbon,” as used herein, represents a group consisting only of carbon and hydrogen atoms.
  • hydroxy represents an -OH group.
  • the hydroxy group can be substituted with 1 , 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.
  • isomer means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • stereoisomers such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • the chemical structures depicted herein, and therefore the compounds of the invention encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
  • Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • V-protected amino refers to an amino group, as defined herein, to which is attached one or two /V-protecting groups, as defined herein.
  • V-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used /V-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • /V-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butyl acetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, and phenylalanine; sulfonyl-containing groups such as benzenesulfonyl, and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl
  • Preferred /V-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).
  • nitro represents an -NO2 group.
  • O-protecting group represents those groups intended to protect an oxygen containing (e.g., phenol, hydroxyl, or carbonyl) group against undesirable reactions during synthetic procedures. Commonly used O-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis,” 3 rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference.
  • O-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, f-butyldimethylsilyl, tri-/so- propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl,
  • alkylcarbonyl groups such as acyl, acetyl, propionyl, and pivaloyl ; optionally substituted arylcarbonyl groups, such as benzoyl ; silyl groups, such as trimethylsilyl (TMS), tert- butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS); ether-forming groups with the hydroxyl, such methyl, methoxymethyl, tetrahydropyranyl, benzyl, p-methoxybenzyl, and trityl ; alkoxycarbonyls, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-isopropoxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-but
  • haloalkoxycarbonyls such as 2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, and 2,2,2-trichloroethoxycarbonyl ; optionally substituted arylalkoxycarbonyl groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl, p- chlorobenzyl
  • tetrahydrofuranyl ethoxyethyl; 1 -[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p- chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl ; triisopropylsilyl ; dimethylisopropylsilyl; t-butyldimethylsilyl ; t-butyldiphenylsilyl ; tribenzylsilyl; triphenylsilyl; and diphenymethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9- fluorenylmethyl ; ethyl ; 2,2,2-trichloroethy
  • carbonyl-protecting groups e.g., acetal and ketal groups, such as dimethyl acetal, and 1 ,3-dioxolane
  • acylal groups e.g., acetal and ketal groups, such as dimethyl acetal, and 1 ,3-dioxolane
  • dithiane groups such as
  • O- and N-protecting groups include: Acetyl (Ac); Acylals; Benzoyl (Bz); Benzyl (Bn, Bnl); Benzyl esters; Carbamate; Carbobenzyloxy (Cbz); Dimethoxytrityl, [6/ ' s-(4-methoxyphenyl)phenylmethyl] (DMT); Dithianes; Ethoxyethyl ethers (EE); Methoxymethyl ether (MOM); Methoxytrityl [(4- methoxyphenyl)diphenylmethyl], (MMT); Methyl Ethers; Methyl (Me); Methyl esters; Methylthiomethyl ether; Orthoesters; Oxazoline; Pivaloyl (Piv); Phthalimido; p-Methoxybenzyl carbonyl (Moz or MeOZ); p- Methoxybenzyl (PMB); Propargyl
  • perfluoro represents anyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical.
  • perfluoroalkyl groups are exemplified by trifluoromethyl, and pentafluoroethyl.
  • protected hydroxyl refers to an oxygen atom bound to an O-protecting group.
  • spirocyclyl represents a C2-7 alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group, and also a C1-6 heteroalkylene diradical, both ends of which are bonded to the same atom.
  • the heteroalkylene radical forming the spirocyclyl group can containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the spirocyclyl group includes one to seven carbons, excluding the carbon atom to which the diradical is attached.
  • the spirocyclyl groups of the invention may be optionally substituted with 1 , 2, 3, or 4 substituents provided herein as optional substituents for cycloalkyl and/or heterocyclyl groups.
  • stereoisomer refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemical ⁇ and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.
  • sulfonyl represents an -S(0)2- group.
  • cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukimias, and lymphomas.
  • Cell migration involves the invasion by the cancer cells into the surrounding tissue and the crossing of the vessel wall to exit the vasculature in distal organs of the cancer cell.
  • cell migration cancers cancers that migrate by invasion by the cancer cells into the surrounding tissue and the crossing of the vessel wall to exit the vasculature in distal organs of the cancer cell.
  • drug resistant cancer refers to any cancer that is resistant to an antiproliferative in Table 1 1 .
  • metalastatic nodule refers to an aggregation of tumor cells in the body at a site other than the site of the original tumor.
  • metastatic tumor refers to a tumor or cancer in which the cancer cells forming the tumor have a high potential to or have begun to, metastasize, or spread from one location to another location or locations within a subject, via the lymphatic system or via haematogenous spread, for example, creating secondary tumors within the subject. Such metastatic behavior may be indicative of malignant tumors. In some cases, metastatic behavior may be associated with an increase in cell migration and/or invasion behavior of the tumor cells.
  • cancers that can be defined as metastatic include but are not limited to non-small cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, biliary tract cancer, bladder cancer, brain cancer including glioblastomas and medullablastomas, cervical cancer, choriocarcinoma, endometrial cancer, esophageal cancer, gastric cancer, hematological neoplasms, multiple myeloma, leukemia, intraepithelial neoplasms, livercancer, lymphomas, neuroblastomas, oral cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer including melanoma, basocellular cancer, squamous cell cancer, testicular cancer, stromal tumors, germ cell tumors, thyroid cancer, and renal cancer.
  • mirating cancer refers to a cancer in which the cancer cells forming the tumor migrate and subsequently grow as malignant implants at a site other than the site of the original tumor.
  • the cancer cells migrate via seeding the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces to spread into the body cavities; via invasion of the lymphatic system through invasion of lymphatic cells and transport to regional and distant lymph nodes and then to other parts of the body; via haematogenous spread through invasion of blood cells; or via invasion of the surrounding tissue.
  • Migrating cancers include metastatic tumors and cell migration cancers, such as ovarian cancer, mesothelioma, and primary lung cancer, each of which is characterized by cellular migration.
  • Non-metastatic cell migration cancer refers to cancers that do not migrate via the lymphatic system or via haematogenous spread.
  • slowing the spread of metastasis refers to reducing or stopping the formation of new loci; or reducing, stopping, or reversing the tumor load.
  • slowing the spread of migrating cancer refers to reducing or stopping the formation of new loci; or reducing, stopping, or reversing the tumor load.
  • substantially enantiomerically pure refers to a composition (e.g., a pharmaceutical composition) wherein greater 85% (e.g., greater than 90%, greater than 95%, up to and including 100%, i.e., within the limits of detection) of the molecules of creatine transport inhibitor or creatine kinase inhibitor in the composition have the same chirality sense.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • “Palliating" a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • tumor seeding refers to the spillage of tumor cell clusters and their subsequent growth as malignant implants at a site other than the site of the original tumor.
  • Figures 1 A-E are a set of diagrams and photographs showing that miR-483-5p, miR-551 a and CKB are clinically relevant and can be therapeutically inhibited, a, miR-483-5p and miR-551 a levels in 37 primary tumor samples and 30 liver metastases samples were quantified by quantitative real-time PCR. b, CKB expression levels in 37 primary tumor samples and 30 liver metastases samples were measured by quantitative real-time PCR.
  • c Liver metastasis in mice injected with LvM3b cells and treated with a single dose of AAV doubly expressing miR-483-5p and miR-551 a one day after injection cells
  • d Bioluminescent measurements of liver metastasis in mice injected with 5 X 10 5 LvM3b cells and treated with cyclocreatine daily for two weeks. Mice were euthanized and livers excised for ex vivo imaging at the end of the treatment, e, Bioluminescent measurements of liver metastasis in mice injected with 5 X 10 5 LvM3b cells and treated with the creatine transporter inhibitor beta-guanidinopropionic acid ( ⁇ -GPA) daily for two weeks. Error bars, s.e.m; all P values are based on one-sided Student's t-tests. * P ⁇ 0.05; ** P ⁇ 0.001 ; *** P ⁇ 0.0001 .
  • FIG. 2 is a diagram and a photograph showing that ⁇ -GPA treatment suppressed colorectal cancer metastasis.
  • FIGS 3A-C are a set of diagrams and photographs showing that creatine transporter, SLC6a8 is required for colorectal and pancreatic cancer metastasis, a) Liver metastasis by highly aggressive LvM3b cells expressing short hairpins targeting the creatine transporter channel, SLC6a8. Liver metastasis were monitored by bioluminescent imaging and mice were euthanized three weeks after inoculation of cancer cells. Livers were extracted for gross histology, b) Liver metastasis in mice injected with 5 X 10 5 SW480 cells transduced with a shRNA targeting SLC6a8. Metastatic progression was monitored by bioluminescent imaging.
  • mice were euthanized 28 days after injection and livers excised for bioluminescent imaging and gross histology, c) Liver metastasis in mice injected with 5 X 10 5 PANC1 pancreatic cancer cells transduced with a shRNA targeting SLC6a8. Metastatic progression was monitored by bioluminescent imaging and mice were euthanized as described above. Error bars represent the s.e.m; all P values are based on one-sided Student's t-tests. * P ⁇ 0.05; ** P ⁇ 0.001 ; *** P ⁇ 0.0001 .
  • Figure 4 is a diagram showing that SLC6a8 is up-regulated in liver metastases compared to primary tumors. Expression of SLC6a8 in 36 primary tumors and 30 liver metastases were quantified by quantitative real-time PCR. Error bars represent the s.e.m; all P values are based on one-sided Student's t-tests. * P ⁇ 0.05.
  • Figure 5 is a diagram and a photograph showing that ⁇ -GPA treatment suppresses survival of disseminated PANC1 pancreatic cancer cells in the liver in vivo.
  • Figure 6 is a diagram showing that ⁇ -GPA enhances the cytotoxicity of Gemcitabine on PANC1 pancreatic cancer cells.
  • Figure 7 is a diagram showing that ⁇ -GPA enhances the cytotoxicity of 5'-fluorouracil on LS-LvM3b colorectal cancer cells.
  • the present invention features methods for preventing or reducing aberrant proliferation, differentiation, or survival of cells.
  • compounds of the invention may be useful in reducing the risk of, or preventing, tumors from increasing in size or from reaching a metastatic state.
  • the subject compounds may be administered to halt the progression or advancement of cancer.
  • the instant invention includes use of the subject compounds to reduce the risk of, or prevent, a recurrence of cancer.
  • the invention features compounds useful in the treatment of cancer.
  • Exemplary compounds described herein include compounds havin according to Formulae l-l l l as described herein:
  • X 1 is absent, NH, or CH2;
  • R 1 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl;
  • R 2 , R 3 , and R 4 are independently hydrogen or optionally substituted C1 -C6 alkyl; and
  • R 5 and R 6 are hydrogen or NH2;
  • R 5 and R 6 are both hydrogen or R 5 is NH2 and R 6 is hydrogen then R 2 is optionally substituted C1 -C6 alkyl,
  • Q 1 is optionally substituted amidino or optionally substituted 2-pyridyl
  • X 2 is S or NR 12 ;
  • n 0 or 1 ;
  • R 7 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl;
  • R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH2, optionally substituted C1 -C6 alkyl, or R 8 or R 9 can combine with R 10 or R 1 1 to form an optionally substituted C3-C6 cycloalkyi ring or with R 12 to form an optionally substituted C3-C6 heterocycle;
  • R 10 and R 1 1 are independently hydrogen, deuterium, optionally substituted C1 -C6 alkyl, or R 10 or R 1 1 can combine with R 8 or R 9 to form an optionally substituted C3-C6 cycloalkyi ring;
  • R 12 is hydrogen, optionally substituted C1 -C6 alkyl, or R 12 can combine with R 8 or R 9 to form an optionally substituted C3-C6 heterocycle, and
  • R 9 is halo then R 8 is halo or optionally substituted C1 -C6 alkyl
  • Q 1 is optionally substituted amidino or optionally substituted 2-pyridyl
  • n 1 or 2;
  • R 7 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl;
  • R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH2, optionally substituted C1 -C3 alkyl, or R 8 and R 9 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyi ring; or R 8 or R 9 combine with R 10 or R 1 1 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyi ring; or R 8 or R 9 combine with R 12 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle;
  • R 10 and R 1 1 are independently hydrogen, deuterium, optionally substituted C1 -C4 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl or R 10 and R 1 1 combine with the atoms to which they are attached to form an optionally substituted C3-C6 cycloalkyi ring; or R 10 or R 1 1 combine with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C3-C4 cycloalkyi ring; or R 10 or R 1 1 combine with R 12 with the atoms to which they are attached to form an optionally substituted C3-C4 heterocycle; R 12 is hydrogen, optionally substituted C1 -C6 alkyl, or R 12 combines with R 8 or R 9 with the atoms to which they are attached to form an optionally substituted C3-C5 heterocycle, or R 12 combines with R 10 or R 1 1 with the atoms to which they are attached to form an
  • R 8 is hydrogen, halo, hydroxyl, or methyl then at least one of R 9 , R 10 , and R 1 1 i: not hydrogen;
  • R 8 is NH2 and R 10 is hydrogen, methyl, or -CH2CH2OH then at least one of R 9 or R 1 1 is not hydrogen;
  • R 8 is halo, and R 10 is optionally substituted C1 -C4 alkyl then at least one of R 9 and R 10 is not hydrogen;
  • A is a inhibitor of creatine transport and/or creatine kinase comprising an amidino group
  • B has the structure:
  • n 0 or 1 ;
  • Q 2 is hydroxyl, optionally substituted amino, or -SO2OH
  • Compounds 1 -448 of Tables 1 -1 1 can also be used for the treatment of certain conditions such as cancer.
  • Creatine helps supply energy to all cells in the body by increasing formation of ATP. It is taken up by tissues with high energy demands through an active transport system. The conversion of ADP to ATP by phosphate transfer from phosphocreatine is catylzed by creatine kinase. Some of the functions associated with the phosphocreatine system include efficient regeneration of energy in the form of ATP in cells with fluctuating and high energy demand, energy transport to different parts of the cell, phosphoryl transport activity, ion transport regulation, and involvement in signal transduction pathways.
  • Creatine kinase has been shown to have elevated levels in certain tumor types. These tumor types may utilize the increased expression of creatine kinase to prevent apoptosis under hypoxic or hypoglycemic conditions. Malignant cancers with poor prognosis have also been shown to overexpress creatine kinases, which may be related to high energy turnover and failure to eliminate cancer cells by apoptosis. Inhibtion of the active transport of creatine into cancer cells may reverse these trends and result in inhibition of the cancer and/or metastasis. Treatment Methods
  • inhibition of creatine transport and/or creatine kinase suppresses metastasis.
  • the phosphocreatine system promotes metastasis by enhancing the survival of disseminated cancer cells in the liver by acting as an energetic store for ATP generation to endure hepatic hypoxia.
  • Inhibition of creatine transport into cancer cells limits the amount of phosphocreatine available to use in the production of ATP.
  • Inhibition of creatine kinase inhibits the production of ATP through conversion of phosphocreatine to creatine.
  • Typical vascularized tumors that can be treated with the method include solid tumors, particularly carcinomas, which require a vascular component for the provision of oxygen and nutrients.
  • Exemplary solid tumors include, but are not limited to, carcinomas of the lung, breast, bone, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, glioblastomas, neuroblastomas, Kaposi's sarcoma, and sarcomas.
  • Treating cancer can result in a reduction in size or volume of a tumor.
  • tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment.
  • Size of a tumor may be measured by any reproducible means of measurement.
  • the size of a tumor may be measured as a diameter of the tumor or by any reproducible means of measurement.
  • Treating cancer may further result in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater (e.g., 1 0%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).
  • Treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site.
  • the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment.
  • the number of metastatic noduless may be measured by any reproducible means of measurement.
  • the number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x).
  • Treating cancer can result in an increase in average survival time of a population of subjects treated according to the present invention in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days).
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the invention.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the compound of the invention.
  • Treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population.
  • the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%).
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with the compound of the invention.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with the compound of the invention.
  • compositions that contains a suitable carrier and one or more of the therapeutic agents described above.
  • the composition can be a pharmaceutical composition that contains a pharmaceutically acceptable carrier, a dietary composition that contains a dietarily acceptable suitable carrier, or a cosmetic composition that contains a cosmetically acceptable carrier.
  • composition refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • a “pharmaceutically acceptable carrier,” after administered to or upon a subject, does not cause undesirable physiological effects.
  • the carrier in the pharmaceutical composition must be “acceptable” also in the sense that it is compatible with the active ingredient and can be capable of stabilizing it.
  • One or more solubilizing agents can be utilized as pharmaceutical carriers for delivery of an active compound.
  • a pharmaceutically acceptable carrier include, but are not limited to, biocompatible vehicles, adjuvants, additives, and diluents to achieve a composition usable as a dosage form.
  • examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. For example, S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1 -19 (1977), incorporated herein by reference.
  • suitable pharmaceutically acceptable salts thereof may, include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • compositions of the present invention additionally include a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, and lubricants, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil ; olive oil; corn oil and soybean oil ; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; natural and synthetic phospholipids, such as soybean and egg yolk phosphatides, lecithin, hydrogenated soy lecithin, dimyristoyi lecithin, dipalmitoyi lecithin, distearoyi lecithin, dioleoyi
  • lecithin which are preferred include those which are available under the trade name Phosal® or Phospholipon® and include Phosal 53 MCT, Phosal 50 PG, Phosal 75 SA, Phospholipon 90H, Phospholipon 90G and Phospholipon 90 NG; soy-phosphatidylcholine (SoyPC) and DSPE-PEG2000 are particularly preferred; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • buffering agents such as magnesium hydroxide and aluminum hydrox
  • compositions in any of the forms described above, can be used for treating melanoma, or any other disease or condition described herein.
  • An effective amount refers to the amount of an active compound/agent that is required to confer a therapeutic effect on a treated subject. Effective doses will vary, as recognized by those skilled in the art, depending on the types of diseases treated, route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatment.
  • a pharmaceutical composition of this invention can be administered parenterally, orally, nasally, rectally, topically, or buccally.
  • parenteral refers to subcutaneous, intracutaneous, intravenous, intrmuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection, as well as any suitable infusion technique.
  • a sterile injectable composition can be a solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • solutions include, but are not limited to, 1 ,3-butanediol, mannitol, water, Ringer's solution, and isotonic sodium chloride solution.
  • fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acid such as, but not limited to, oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as, but not limited to, olive oil or castor oil, polyoxyethylated versions thereof.
  • oil solutions or suspensions also can contain a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents.
  • a long chain alcohol diluent or dispersant such as, but not limited to, carboxymethyl cellulose, or similar dispersing agents.
  • Other commonly used surfactants such as, but not limited to, Tweens or Spans or other similar emulsifying agents or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms also can be used for the purpose of formulation.
  • a composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions.
  • commonly used carriers include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as, but not limited to, magnesium stearate, also are typically added.
  • useful diluents include, but are not limited to, lactose and dried corn starch.
  • compositions for topical administration can be formulated as solutions, ointments, creams, suspensions, lotions, powders, pastes, gels, sprays, aerosols, or oils.
  • topical formulations can be in the form of patches or dressings impregnated with active ingredient(s), which can optionally include one or more excipients or diluents.
  • active ingredient(s) which can optionally include one or more excipients or diluents.
  • the topical formulations include a material that would enhance absorption or penetration of the active agent(s) through the skin or other affected areas.
  • a topical composition contains a safe and effective amount of a dermatologically acceptable carrier suitable for application to the skin.
  • a "cosmetically acceptable” or “dermatologically-acceptable” composition or component refers a composition or component that is suitable for use in contact with human skin without undue toxicity, incompatibility, instability, or allergic response.
  • the carrier enables an active agent and optional component to be delivered to the skin at an appropriate concentration(s).
  • the carrier thus can act as a diluent, dispersant, solvent, or the like to ensure that the active materials are applied to and distributed evenly over the selected target at an appropriate concentration.
  • the carrier can be solid, semi-solid, or liquid.
  • the carrier can be in the form of a lotion, a cream, or a gel, in particular one that has a sufficient thickness or yield point to prevent the active materials from sedimenting.
  • the carrier can be inert or possess dermatological benefits. It also should be physically and chemically compatible with the active components described herein, and should not unduly impair stability, efficacy, or other use benefits associated with the composition. Combination Therapies
  • the pharmaceutical composition may further include an additional compound having antiproliferative activity.
  • the additional compound having antiproliferative activity can be selected from a group of antiproliferative agents including those shown in Table 12.
  • compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
  • the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).
  • antiproliferative agent any antiproliferative agent, including those antiproliferative agents listed in Table 12, any of which can be used in combination with a creatine transport and/or creatine kinase inhibitor to treat the medical conditions recited herein.
  • Antiproliferative agents also include organo- platine derivatives, naphtoquinone and benzoquinone derivatives, chrysophanic acid and anthroquinone derivatives thereof.
  • Alkylating agents Busulfan Chlorambucil
  • 6-mercaptopurine hydroxyurea 6-thioguanine decitabine (SuperGen) cytarabine clofarabine (Bioenvision) 2-fluorodeoxy cytidine irofulven (MGI Pharma) methotrexate DMDC (Hoffmann-La Roche) tomudex ethynylcytidine (Taiho) fludarabine gemcitabine raltitrexed capecitabine
  • etoposide gimatecan (Sigma-Tau) teniposide or mitoxantrone diflomotecan (Beaufour-lpsen) 7-ethyl-10-hydroxy-camptothecin TAS-103 (Taiho)
  • NCI dolastatin 10
  • TXD 258 (Aventis) combretastatin A4 (BMS) epothilone B (Novartis) isohomohalichondrin-B (PharmaMar)
  • Fabre vinflunine
  • AVLB Prescient NeuroPharma
  • auristatin PE Teikoku Hormone
  • azaepothilone B BMS
  • glufosfamide (Baxter International) mafosfamide (Baxter International) albumin + 32P (Isotope Solutions) apaziquone (Spectrum
  • TNF alpha virulizin (Lorus Therapeutics) revimid (Celgene)
  • Immuno-modulators interferon dexosome therapy (Anosys) oncophage (Antigenics) pentrix (Australian Cancer
  • CTL Immuno melanoma vaccine
  • Dovetail ⁇ -alethine
  • p21 RAS vaccine GamVax
  • CLL therapy Vasogen
  • Photodynamic talaporfin (Light Sciences) Pd-bacteriopheophorbide (Yeda) agents Theralux (Theratechnologies) lutetium texaphyrin (Pharmacyclics) motexafin gadolinium hypericin
  • SR-27897 CK A inhibitor, Sanofi-Synthelabo ceflatonin (apoptosis promotor, ChemGenex) tocladesine (cyclic AMP agonist, Ribapharm) BCX-1777 (PNP inhibitor, BioCryst) alvocidib (CDK inhibitor, Aventis) ranpirnase (ribonuclease stimulant, Alfacell) CV-247 (COX-2 inhibitor, Ivy Medical) galarubicin (RNA synthesis inhibitor, Dong-A) P54 (COX-2 inhibitor, Phytopharm) tirapazamine (reducing agent, SRI
  • GCS-100 gal3 antagonist, GlycoGenesys
  • N-acetylcysteine reducing agent, Zambon
  • G17DT immunogen Gastrin inhibitor, Aphton
  • R-flurbiprofen NF-kappaB inhibitor, Encore
  • efaproxiral oxygenator, Alios Therapeutics
  • 3CPA NF-kappaB inhibitor, Active Biotech
  • PI-88 heparanase inhibitor, Progen
  • seocalcitol vitamin D receptor agonist, Leo
  • tesmilifene histamine antagonist, YM 131 -I-TM-601 (DNA antagonist,
  • histamine histamine H2 receptor agonist, Maxim
  • ODC inhibitor eflornithine
  • tiazofurin IMPDH inhibitor
  • Ribapharm tiazofurin
  • minodronic acid osteoclast inhibitor, cilengitide (integrin antagonist, Merck KGaA) Yamanouchi
  • SR-31747 (IL-1 antagonist, Sanofi-Synthelabo) indisulam (p53 stimulant, Eisai)
  • CCI-779 mTOR kinase inhibitor, Wyeth
  • PPT inhibitor PharmaMar
  • exisulind PDE V inhibitor, Cell Pathways
  • gemtuzumab CD33 antibody, Wyeth Ayerst
  • CP-461 PDE V inhibitor, Cell Pathways
  • PG2 hematopoiesis enhancer
  • WX-UK1 plasmaogen activator inhibitor, Wilex
  • ImmunolTM triclosan oral rinse, Endo
  • PBI-1402 PMN stimulant, ProMetic LifeSciences
  • triacetyluridine uridine prodrug , Wellstat
  • bortezomib proteasome inhibitor, Millennium
  • SRL-172 T cell stimulant, SR Pharma) Bioscience
  • TLK-286 glutthione S transferase inhibitor, TransMID-107TM (immunotoxin, KS Biomedix) Telik
  • PCK-3145 apoptosis promotor, Procyon
  • PT-100 growth factor agonist, Point doranidazole (apoptosis promotor, Pola)
  • BRAF inhibitors BRAF inhibitors
  • PDL1 inhibitors urocidin apoptosis promotor, Bioniche
  • carmustine Ro-31 -7453 apoptosis promotor, La Roche
  • Mitoxantrone brostallicin (apoptosis promotor, Pharmacia)
  • CTLA-4 inhibitors CTLA-4 inhibitors
  • rituximab CD20 antibody, Genentech sorafenib
  • CHS-828 cytotoxic agent, Leo
  • bryostatin-1 PLC stimulant, GPC Biotech
  • trans-retinoic acid differentially retinoic acid
  • CDA-II apoptosis promotor, Everlife
  • MX6 apoptosis promotor, MAXIA
  • SDX-101 apoptosis promotor, Salmedix
  • apomine apoptosis promotor, ILEX Oncology
  • X 1 is absent, NH, or CH2;
  • R 1 is hydrogen, optionally substituted C1 -C6 alkyi, or optionally substituted C6-C10 aryl C1 -C6 alkyi;
  • R 2 , R 3 , and R 4 are independently hydrogen or optionally substituted C1 -C6 alkyi;
  • R 5 and R 6 are hydrogen or NH2
  • R 5 and R 6 are both hydrogen or R 5 is NH2 and R 6 is hydrogen then R 2 is optionally substituted C1 -C6 alkyi,
  • R 2 is hydrogen or optionally substituted C1 -C6 alkyi, wherein said optionally substituted C1 -C6 alkyi is methyl, ethyl, isopropyl, propyl, isobutyl, or optionally substituted C1 -C6 haloalkyl.
  • Q 1 is optionally substituted amidino or optionally substituted 2-pyridyl
  • X 2 is S or NR 12 ;
  • n 0 or 1 ;
  • R 7 is hydrogen, optionally substituted C1 -C6 alkyl, or optionally substituted C6-C10 aryl C1 -C6 alkyl;
  • R 8 and R 9 are independently hydrogen, deuterium, halo, hydroxyl, NH2, optionally substituted C1 -C6 alkyl, or R 8 or R 9 can combine with R 10 or R 1 1 to form an optionally substituted C3-C6 cycloalkyi ring or with R 12 to form an optionally substituted C3-C6 heterocycle;
  • R 10 and R 1 1 are independently hydrogen, deuterium, optionally substituted C1 -C6 alkyl, or R 10 or R 1 1 can combine with R 8 or R 9 to form an optionally substituted C3-C6 cycloalkyi ring;
  • R 12 is hydrogen, optionally substituted C1 -C6 alkyl, or R 12 can combine with R 8 or R 9 to form an optionally substituted C3-C6 heterocycle,
  • R 12 is hydrogen
  • R 9 is halo then R 8 is halo or optionally substituted C1 -C6 alkyl
  • A is a inhibitor of creatine transport comprising an amidino group
  • n 0 or 1 ;
  • Q 2 is hydroxyl, optionally substituted amino, or -SO2OH
  • a method for treating cancer comprising administering to a subject in need thereof, a compound of any one of embodiments 1 -64 in an amount sufficient to treat said cancer.
  • a method of slowing the spread of a migrating cancer comprising administering to a subject in need thereof, a compound of any one of embodiments 1 -64 in an amount sufficient to slow the spread of said migrating cancer.
  • said method comprises the suppression of metastatic colonization of said migrating cancer in the liver.
  • metastatic cancer comprises cells exhibiting endothelial recruitment and/or angiogenesis.
  • a method for inhibiting proliferation or growth of cancer stem cells or cancer initiating cells comprising contacting the cell with a compound of any one of embodiments 1 -64 in an amount sufficient to inhibit proliferation or growth of said cell.
  • a method of reducing the rate of tumor seeding of a cancer comprising administering to a subject in need thereof a compound of any one of embodiments 1 -64 in an amount sufficient to reduce tumor seeding.
  • a method of reducing or treating metastatic nodule-forming of cancer comprising administering to a subject in need thereof a compound of any one of embodiments 1 -64 in an amount sufficient to treat said metastatic nodule-forming of cancer.
  • any one of embodiments 65-79 wherein said cancer is breast cancer, colon cancer, renal cell cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, esophageal cancer, prostate cancer, sarcoma, or melanoma.
  • said cancer is gastrointestinal cancer.
  • gastrointestinal cancer is esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer, anal cancer, mucosa- associated lymphoid tissue cancer, gastrointestinal stromal tumors, a cancer of the biliary tree, or a gastrointestinal carcioid tumor.
  • Ramucirumab Tivozanib, Stivarga, CRS-207, or a PD-1 or PDL-1 antibody.
  • a method of treating metastatic cancer in a subject in need thereof comprising:
  • a method for treating metastatic cancer in a subject in need thereof comprising contacting creatine transport channel SLC6a8 with a compound of any one of embodiments 1 -64 in an amount effective to suppress metastatic colonization of said cancer.
  • Indicated cell-lines were purchased from ATCC and cultured in DMEM media supplemented with
  • 100K cells were seeded in triplicates in 6 well plates and cells were counted 5 days after seeding. Cells were cultured in cell culture chamber containing 1 % oxygen.
  • mice 5x10 5 highly metastatic cancer cells were injected into the portal circulation of immunodeficient mice.
  • mice were injected indicated amounts of drug in 300 ⁇ _ PBS.
  • Treatment was continued daily and metastatic progression was monitored by bioluminescent imaging until the mice were euthanized at which point livers were excised for bioluminescent imaging and gross histology.
  • cancer cells were pre-treated with indicated amounts of compound for 48hrs before injection into immunodeficient mice.
  • Soluble compounds were formulated in saline solution (0.9% NaCI). Some compounds were first dissolved 1 N hydrochloric acid (1 .0 equivalent) to make the HCI salt followed by addition of PBS to adjust to the final volume. Less soluble compounds were first dissolved 1 or 2 N hydrochloric acid (1 .0 equivalent) to make the HCI salt followed by addition of DMSO and water to adjust to the final volume resulting in a 1 :1 DMSO to aqueous ratio.
  • mice were weighed and randomly divided into groups of 3 mice per group and injected i.p. with 1 00-200 [it of dosing solution to deliver 250 mg/kg (50 mg/mL or 381 mM) ⁇ -GPA equivalent (i.e. 1 .91 mmol/kg) along with a vehicle control. Creatine-(methyl-cfe) monohydrate (i.e.
  • Mouse hearts were thawed and weighed into 1 .5 mL Eppendorf conical tubes. Typical heart weights range from 800 - 1200 mg. Between six to twelve 1 mm zirconia/silica beads (BioSpec Products, Inc., Bartlesville, OK) were added to the tubes with sufficient volume of 70% 2-propanol in water to afford a 4-fold dilution. The samples were then placed in a MiniBeadBeater (BioSpec Products, Inc.) for 2 minutes to disrupt the tissue and homogenize the sample.
  • MiniBeadBeater BioSpec Products, Inc.
  • Calibration standards, blanks, and quality control samples are prepared from control mouse hearts homogenized as noted above. Aliquots of homogenate were then spiked with known quantities of creatine- cfe (CDN Isotopes, Pointe-Claire, Quebec) or solvent, and processed along with the samples as noted above.
  • CDN Isotopes Pointe-Claire, Quebec
  • Quad 5500 (AB Sciex, Framingham, MA) system. Five microliters of sample are injected onto a HILIC column, 2.1 x 50 mm, 3 ⁇ (Fortis Technologies, Cheshire, England) at a flow rate of 0.4 mL/min. A binary gradient of acetonitrile and 10 mM ammonium acetate was used to elute analytes from the column. The mass spectrometer was operated in positive ion electrospray in Multiple Reaction Monitoring mode for the following mass transitions:
  • Creatine-cfe m/z 137.1 /95.0
  • Creatine-cfe m/z 135.1 /93.0
  • LS174T cells expressing a luciferase reporter were suspended in a volume of 20 ⁇ 1 :1 PBS/Matrigel mixture and injected intra-hepatically into the livers of NOD-SCID mice.
  • Metastatic nodules were allowed to develop over a period of 3-4 weeks and monitored by bioluminescence imaging. Nodules formed were excised and dissociated by collagenase and hyaluronidase digestion into single cell suspension. The cells were allowed to expand in in vitro before re-injection into mice. After three reiterations of in vivo selection, highly metastatic LvM3a and LvM3b derivative cell-lines were established.
  • lentivirus Lenti-miR library of 61 1 miRNAs System Biosciences
  • MOI multiplicity of infection
  • the transduced population was then injected intra-hepatically into NOD-SCID mice for in vivo selection of miRNAs that when over-expressed, either promoted or suppressed metastatic liver colonization.
  • Genomic DNA PCR amplication and recovery of lenti-viral miRNA inserts were performed on cells prior to injection and from liver nodules according to manufacturer's protocol. miRNA array profiling allowed for miRNA insert quantification prior to and after in vivo selection.
  • livers to be injected were labeled with cell-tracker red or green (Invitrogen) and inoculated into livers of NOD-SCID mice through intrasplenic injection.
  • the livers were then extracted and cut into 1 50um slices using a Mcllwain tissue chopper (Ted Pella) and plated onto organotypic tissue culture inserts (Millipore) and cultured in William's E Medium supplemented with Hepatocyte Maintenance Supplement Pack (Invitrogen). After indicated time periods, the liver slices were fixed in paraformaldehyde and imaged using multi-photon microscopy.
  • luciferin is inactive until the DEVD peptide is cleaved from by activated caspase-3 in apoptotic cells.
  • DEVD-luciferin was injected into mice bearing colorectal cancer cells expressing luciferase. Upon activation by apoptotic cells, bioluminescence imaging can be performed to measure caspase activity in vivo. Five hours after in vivo caspase activity measurement, mice are injected with regular luciferin for normalization purposes.
  • miR-483-5p and miR-551 a were cloned as a polycistron consisting of both miRNA precursor with flanking genomic sequences in tandem into the Bglll and Notl site of scAAV.GFP (Plasmid 21893, Addgene). Listed below are genomic sequences encoding for miR-483-5p and miR-551 a (SEQ ID NOs: 5 and 6), corresponding precursor sequences (underlined, SEQ ID NOs: 3 and 4), and corresponding mature microRNA sequences (underlined and in bold, SEQ ID NOs: 1 and 2). Adeno-associated viruses were packaged, purified and titered using the AAV-DJ Helper Free expression system from Cell Biolabs.
  • pLKO vectors expressing shRNA hairpins targeting CKB and SLC6a8 were ordered from Sigma-
  • mice were treated with 10mg of cyclocreatine or saline vehicle, administered through intra-peritoneal injection.
  • the treatment regime started one day after inoculation of tumor cells and continued until the mice were euthanized.
  • Beta-guanidipropionic acid was administered at a dose of 200 ⁇ _ of 0.5M solution through intra-peritoneal injection.
  • Treatment regime were as that for cyclocreatine treatment.
  • Compounds of the invention may be synthesized using methods known in the art, for example using methods described in U.S. Patent Nos. 5,321 ,030, 5,324,731 , 5,955,617, 5,994,577, or 5,998,457 or methods described in Metabolism 1980, 29 (7), 686, J. Med. Chem. 2001 , 44, 1231 , J. Biol. Chem. 1972, 247, 4382, J. Chem. Inf. Model. 2008, 48 (3), 556, or J. Med. Chem. 2001 , 44, 1217.
  • the compounds of the invention may be synthesized using the methods described below.
  • Cyclocreatine analogs may be made from amino carboxylic acids or esters and reaction with aziridines in inert solvents (e.g. diethyl ether, THF, DME, ethanol, DMF, THF, etc.). These diamine intermediates are then reacted with cyanogen bromide in inert solvent (e.g. diethyl ether, THF, DMF, etc.) to form iminoimidazolidine desired products.
  • inert solvents e.g. diethyl ether, THF, DME, ethanol, DMF, THF, etc.
  • Iminohexahydropyrimidine analogs may be made from a-halo carboxylic acids or esters and reaction with 1 ,3-diaminopropanes. These diamine intermediates may be reacted with cyanogen bromide in inert solvent (e.g. diethyl ether, THF, DMF, etc.) to form iminohexahydropyrimidine desired products.
  • inert solvent e.g. diethyl ether, THF, DMF, etc.
  • Dihydrazinyl analogs may be made from a-halo carboxylic acids or esters and reaction with protected hydrazinyl alkyl amino derivatives.
  • Protected hydrazinyl alkyl amino derivatives may be made by reaction of trifluoroacetohydrazide with aziridines or 1 -azido-3-halopropane followed by subsequent azide reduction under standard conditions (e.g. triphenylphosphine-acetone-water). These diamine intermediates may be reacted with 1 ,1 '-thiocarbonyldiimidazole (TCI) in polar solvent (e.g.
  • TCI 1 ,1 '-thiocarbonyldiimidazole
  • the diaminocarboxylic acid or ester intermediates generated above may be reacted with 1 ,1 '- thiocarbonyldiimidazole (TCI) in polar solvent (e.g. DMF, dioxane, etc.) to form imidazolidinethiones or tetrahydro-2-pyrimidinethiones.
  • polar solvent e.g. DMF, dioxane, etc.
  • alkyl halide e.g. methyl iodide
  • subsequent reaction with hydrazine would afford the desired products.
  • Aminoiminoimidazolidine and aminoiminohexahydropyrimidine analogs may be made from a-halo carboxylic acids or esters and reaction with azirindes or azetidines respectively. These a-carboxy aziridines or azetidines are opened with cyanogen bromide to form cyanamide alkyl bromide intermediates (see J. Org. Chem. 1949, 14, 605 and J. Am. Chem. Soc. 2013, 735(41 ), 1 5306). Reaction with hydrazine would afford the desired cyclic products.
  • acetone B2 f3 ⁇ 4B R lmino-1 ,2,4-triazinanes analogs may be made from a-halo carboxylic acids or esters and reaction with protected hydrazinyl alkyl azido derivatives.
  • PMB-protected hydrazinyl alkyl azide derivatives may be prepared as described in Org. Biomol. Chem. 2012, 70(30), 581 1 .
  • the azide is reduced under standard conditions (e.g. triphenylphosphine-acetone-water) and the resulting diamine is treated with cyanogen bromide to form the cyclic core.
  • Deprotection of the PMB hydrazine protecting group under standard conditions e.g. CAN, strong acid, etc.
  • Compounds 226-228 may be synthesized using similar methods as used to make compound 225 by replacing alanine with a-aminobutanoic acid, valine, or isoleucine. Synthesis of Compound 237
  • Compounds 238-240 may be synthesized using similar methods as used to make compound 237 by replacing 2-chloropropanoic acid with 2-chlorobutanoic acid, 2-chloro-3-methylbutanoic acid, or 2-chloro-3- methylpentanoic acid.
  • Step 1 2- ⁇ [2-(trifluoroacetohydrazido)ethyl]amino ⁇ acetic acid (INT-1 )
  • Trifluoroacetohydrazide (2.0 mmol) and aziridine (2.0 mmol) are dissolved in diethyl ether (5 mL) and stirred at room temperature overnight. 2-Chloroacetic acid (2.0 mmol) is added and the mixture stirred 3 h at room temperature. The precipitate is filtered and washed with diethyl ether to afford INT-1 .
  • Step 2 2-[2-sulfanylidene-3-(trifluoroacetamido imidazolidin-1 -yl]acetic acid (INT-2)
  • Diamine INT-1 (1 .5 mmol) is dissolved in DMF (5 mL) and reacted with 1 ,1 '-thiocarbonyldiimidazole (1 .5 mmol) at room temperature for 3 h.
  • the reaction is poured into 0.1 N aqueous HCI, the aqueous layer is extracted with ethyl acetate, the organic layer is dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (10-90 methanol-dichloromethane) to afford INT- 2.
  • INT-2 (1 .0 mmol) is dissolved in ethanol (5 mL) and methyl iodide is added (1 .0 mmol). The mixture is stirred for 1 h at room temperature. Upon completion, hydrazine (5 mmol) is added and the mixture is heated to reflux for 8 h. The mixture is concentrated to remove excess hydrazine, the residue is purified by reverse phase chromatography (acetonitrile/water with 0.05% trifluoroacetic acid), and the product is collected and lyophilized to afford the trifluoroacetate salt of 2-[3-amino-2-hydrazinylideneimidazolidin-1 - yl]acetic acid (229).
  • Compounds 230-228 and 241 -243 may be synthesized using similar methods as used to make compound 229 by replacing chloroacetic acid with 2-chloroacetic acid, 2-chloropropanoic acid, or 2-chloro-3- methylbutanoic acid.
  • aziridine may be replaced with 1 ,3- dibromopropane.
  • Compounds 233 and 244-246 may be synthesized using similar methods to make compound 232 by replacing 2-chloropropanoic acid with 2-chloroacetic acid, or 2-chloro-3-methylbutanoic acid. To synthesize compounds 244-246, aziridine may be replaced with azetidine. Synthesis of Compound 234
  • Step 1 2-(2-sulfanylideneimidazolidin-1 -yl)acetic acid (INT-3)
  • INT-3 (1 .0 mmol) is dissolved in ethanol (5 mL) and methyl iodide is added (1 .0 mmol). The mixture is stirred for 1 h at room temperature. Upon completion, hydrazine (5 mmol) is added and the mixture is heated to reflux for 8 h. The mixture is concentrated to room excess hydrazine, the residue is purified by reverse phase chromatography (acetonitrile/water with 0.05% trifluoroacetic acid), and the product is collected and lyophilized to afford the trifluoroacetate salt of 2-[2-hydrazinylideneimidazolidin-1 -yl]acetic acid (234).
  • Compounds 235-336 may be synthesized using similar methods to make compound 234 by replacing glycine with alanine or valine.
  • Compounds 247-349 may be synthesized using similar methods to make the diamine intermediate for compound 237 and then following the protocol to make 234.
  • Step 1 1 -(2-azidoethyl)-1 -[(4-methoxyphenyl)methyl]hydrazine (INT-4)
  • Step 3 2-(3-imino-1 ,2,4-triazinan-2-yl)acetic acid (250).
  • Compounds 251 -252 may be synthesized using similar methods to make compound 250 by replacing 2-chloroacetic acid with 2-chloropropanoic acid or 2-chloro-3-methylbutanoic acid.
  • uanidines are made from amines using standard guanylating agents (e.g. 2-methyl-2-thiopseudourea sulfate [MTS], cyanamide, A/,/V-di-Boc-1 -/-pyrazole-1 -carboxamide, etc.).
  • MTS 2-methyl-2-thiopseudourea sulfate
  • a preferred method using MTS is described in J. Med. Chem. 2001 , 44, 1217, J. Chem. Soc. C 1971 , 238 and Tetrahedron Lett. 1996, 37, 2483.
  • amines are dissolved or suspended in basic aqueous alcoholic solvent and reacted with 2- methyl-2-thiopseudourea sulfate (MTS) for 24-72 h or longer and precipitated products are isolated by filtration.
  • ester hydrolysis is done by treatment with hydroxide ion (e.g. LiOH, NaOH, KOH, etc) in aqueous alcoholic solvent or THF, to afford the desired product.
  • hydroxide ion e.g. LiOH, NaOH, KOH, etc
  • W is one or two protection groups (Boc or Cbz)
  • W is one or two protection groups (Boc or Cbz)
  • guanidines are made from amines under anhydrous conditions using pyrazole- activated guanylating agents (e.g. 1 -/-pyrazole-1 -carboxamidine hydrochloride, 3,5-dimethyl-1 - pyrazolylformaminidium nitrate, /V-Boc-1 -/-pyrazole-1 -carboxamidine, /V,/V-di-Boc-1 /-/-pyrazole-1 - carboxamidine, /V-(benzyloxycarbonyl)-1 -/-pyrazole-1 -carboxamidine, and /V,/V-bis(benzyloxycarbonyl)-1 H- pyrazole-1 -carboxamidine).
  • pyrazole-activated guanylating agents e.g. 1 -/-pyrazole-1 -carboxamidine hydrochloride, 3,5-dimethyl-1 - pyrazolylformaminidium nitrate,
  • amino alcohols are used with the method above. After guanylation, the alcohol is oxidized to the carboxylic acid using sodium metaperiodate and ruthenium (III) chloride (catalytic) in acetonitrile, ethyl acetate and water (Org. Lett. 2008, 10, 5155). Finally, standard deprotection conditions are used to remove the guanidine protecting groups (i.e. TFA removal of Boc or hydrogenation of Cbz) to afford the desired product.
  • Aminopyridines may be made utilizing cross-coupling methods as described in J. Am. Chem. Soc.
  • amines, 2-halopyridines, and sufficient base e.g. cesium carbonate, potassium ferf-butoxide, etc.
  • polar solvent e.g. DMF, dioxane
  • catalytic palladium e.g. PdC or Pd(OAc)2
  • phosphine ligand e.g. BINAP
  • ester hydrolysis by treatment with hydroxide ion e.g. LiOH, NaOH, KOH, etc
  • hydroxide ion e.g. LiOH, NaOH, KOH, etc
  • Z represents CF3 amides or Boc or Cbz carbamates
  • Buchwald amide-cross-coupling methods are used to generate desired compounds as described in see J. Am. Chem. Soc. 2002, 124, 1 1684 and J. Am. Chem. Soc. 2001 , 123, 7727. Briefly, amines are protected as amides or carbamates (e.g. trifluoroacetamide, Boc, Cbz, etc.) and reacted with 2- bromopyridine in polar solvent (e.g. dioxane, DMF) with base (e.g.
  • polar solvent e.g. dioxane, DMF
  • Pseudothioureas may be made by reaction of a thiourea with alkylhalides as described in J. Med. Chem. 2001 , 44, 121 7. Briefly, 3-chloropropionic acids or esters may be reacted with thiourea in polar solvent (e.g. acetone) followed by refluxing the mixture for 48 h. 3-Chloropropionic acids or esters may be made by reaction of 3-hydroxypropionic acids with thionyl chloride as described in International Patent Publication No. W09933785.
  • pseudothioureas may be made from amino compounds via alkyl bromides using methods as described in Tetrahedron: Asymmetry 1998, 9(1 0), 1641 and International Patent Publication No. WO2002009705. Briefly, 3-aminocarboxylic acids or esters may be converted to 3-bromocarboxylic acids or esters via activation with sodium nitrite in the presence of hydrobromic acid. The resulting bromo compound may be reacted with a thiourea in a suitable solvent (e.g. toluene or acetone) at greater than 60 °C for 4-24 h. If necessary, ester hydrolysis by treatment with hydroxide ion (e.g. LiOH, NaOH, KOH, etc) in aqueous alcoholic solvent, would afford the desired product.
  • hydroxide ion e.g. LiOH, NaOH, KOH, etc
  • 2-Aminopseudothioureas may be made from aziridines by methods similar to those described in Chem. Comm. 2000, 7, 61 9 and Org. Biomol. Chem. 2005, 3(1 8), 3357. Briefly, A/-Cbz-2-carboxyaziridines may be reacted with thiourea and borontrifluoride-etherate in inert solvent (e.g. chloroform, dichloromethane, etc). Subsequent hydrogenation in the presence of palladium on carbon, and if necessary, ester hydrolysis by treatment with hydroxide ion (e.g. LiOH, NaOH, KOH, etc) in aqueous alcoholic solvent, would afford the desired product. 2-Carboxyaziridines may be made by methods as described in Synlett 2001 , 5, 679 and Tetrahedron Lett. 2006, 47(1 3), 2065 and may be converted to Cbz-protected aziridines by standard methods.
  • inert solvent
  • Step 1 (1 HA ,2,3-benzotriazol-1 -ylmethyl)dibenzylamine (INT-6)
  • the INT-7 (1 .52 g, 4.59 mmol) was dissolved in ethanol (25 mL). Trifluoroacetic acid (0.372 mL, 4.85 mL) and a catalytic amount of palladium hydroxide on carbon was added and the reaction was subjected to hydrogen under atmospheric pressure for 16 h. Subsequently, the catalyst was removed by filteration through celite and washed with ethanol. The resulting filtrate was evaporated under reduced pressure and the residue was treated with toluene (50 mL) and concentrated, this was repeated twice to remove residual solvent and excess water. The residue was dried under high vacuum overnight to afford the INT-8 as a yellowish oil (used as crude in the next step).
  • Step 4 ethyl 3- ⁇ [(1 Z)- ⁇ [(ferf-butoxy)carbonyl]amino ⁇ ( ⁇ [(ferf-butoxy)carbonyl]imino ⁇ )methyl]amino ⁇ -2,2- difluoropropanoate (INT-9)
  • ester in INT-8 is hydrolyzed using lithium hydroxide to make SM05 and the resulting amino acid is guanylated using 1 -/-pyrazole-1 -carboxamidine hydrochloride and diisopropylethylamine in DMF as shown below for compound 261 .
  • 3-Azetidinecarboxylic acid SM06 (2.0 g, 19.8 mmol) was suspended in water (2 mL) and then treated with 10 N sodium hydroxide solution in water (1 .96 mL, 19.6 mmol). The thick yellowish solution was then treated with solid cyanamide (1 .01 g, 24 mmol) and the mixture turned solid instantly. More water (5 mL) was added to ensure adequate stirring and the slurry was then stirred at room temperature for 3 days. The white solid was subsequently filtered off, washed with cold water (10 mL, 0 °C) and then air dried for 2 hours.
  • trans-2- bromocyclobutane-1 -carboxylic acid (2.5 mmol). The reaction is stirred at 60°C for 5 h. The toluene is then removed under reduced pressure and the resulting residue is diluted with water (25 mL) and 1 N hydrochloric acid (30 mL), to achieve pH of 1 -1 .5. The mixture is stirred at room temperature for 1 -2 hours and then extracted with ethyl acetate (3x50 mL). The combined organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure.
  • the resulting solid is dissolved in water (3.0 mL) and filtered through a 0.2 ⁇ nylon filter.
  • the filtrate is purified by preparative HPLC (e.g. Waters PrepPak cartridge Delta-Pak C18 compression column, 15 ⁇ 25x100 mm, 95:5 water-acetonitrile at 12.0 mL/min).
  • the product is collected and lyophilized to afford the product c/ ' s-2-(carbamimidoylsulfanyl)cyclopropane-1 - carboxylic acid (278).
  • Step 1 1 -Benzyl 2-methyl 3-(trifluoromethyl)aziridine-1 ,2-dicarboxylate (INT-10)
  • INT-10 may be made by methods as described in Synlett 2001 , 5, 679 and Tetrahedron Lett. 2006, 47(13), 2065 and converted to a Cbz-protected aziridine by standard methods (see Org. Biomol. Chem. 2005, 3(1 8), 3357).
  • Step 2 methyl 2- ⁇ [(benzyloxy)carbon l]amino ⁇ -3-(carbamimidoylsulfanyl)-4,4,4-trifluorobutanoate (INT-1 1 )
  • INT-10 (1 .0 mmol) is dissolved in dichloromethane (10 mL) and the mixture is cooled to 0 °C.
  • INT-1 1 (0.5 mmol) is dissolved methanol, 10% palladium on carbon (Pd/C 10 mol%) is added and the flask is vacuum purged with hydrogen gas 5 times. The mixture is stirred vigorously at room temperature under a hydrogen atmosphere for 16 h. Nitrogen gas is used to purge the flask and the mixture is filtered through Celite to remove the Pd/C. The mixture is concentrated under reduced pressure, and the residue is treated with 1 N sodium hydroxide in methanol. Once ester hydrolysis is complete, the mixture is concentrated again under reduced pressure, and the resulting residue is dissolved in water (3.0 mL) and filtered through a 0.2 ⁇ nylon filter. The filtrate is purified by preparative HPLC (e.g.
  • Aminopentanoic acid SM37 (500 mg, 4.27 mmol) was converted into the corresponding guanidino derivative according tothe procedure for compound (21 9).
  • the desired compound 358 was obtained as a white powder after high vacuum drying (291 mg, 43%); 1 H-NMR (300 MHz, D 2 0): ⁇ 3.63 (m, 1 H), 2.39 (dd, 1 H), 2.29 (dd, 1 H), 1 .52 (m, 2H), 0.85 (t, 3H); ES(pos) MS m/z 160.1 1 (M+H + ).
  • Step 1 ferf-butyl N-[(1 )- ⁇ [(ferf-butoxy)carbonyl]imino ⁇ [(3-hydroxy-2,2-dimethylpropyl)
  • 3-Amino-2,2-dimethylpropanol SM45 (464 mg, 4.5 mmol) was dissolved in dry THF (7 mL) and then treated with ⁇ /, ⁇ /'-di-Boc-l -/-pyrazole-1 -carboxamidine (1 .24 g, 4.0 mmol). After stirring for 72 hours at room temperature, the reaction mixture was poured into ethyl acetate (200 mL) and then washed with water (2 x 100 mL) adjusting the pH of the aqueous layer to pH 1 -2 using 1 N HCI. The combined aqueous washes were then re-extracted with ethyl acetate (100 mL).
  • INT-12 (1 .30 g, 3.76 mmol) was dissolved in acetonitrile (25 mL), carbon tetrachloride (25 mL), and water (40 mL).
  • Sodium periodate (4.83 g, 22.6 mmol) and ruthenium trichloride (50 mg, catalytic) were added and the mixture was stirred for 3 h at room temperature or until TLC showed starting material had been consumed.
  • the resulting biphasic mixture was poured into ethyl acetate (200 mL) and then washed with water (2 x 100 mL) adjusting the pH of the aqueous layer to pH 1 -2 using 1 N HCI.

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Abstract

La présente invention concerne des composés qui inhibent le transport de la créatine et/ou de la créatine kinase, des compositions pharmaceutiques comprenant de tels composés, ainsi que des méthodes d'utilisation de tels composés et de telles compositions pour le traitement du cancer.
PCT/US2016/030243 2015-04-30 2016-04-29 Inhibiteurs de transport de créatine et leurs utilisations Ceased WO2016176636A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3137447A4 (fr) * 2014-04-30 2018-01-03 Rgenix, Inc. Inhibiteurs de transport de la créatine et leurs utilisations
US10308597B2 (en) 2014-04-30 2019-06-04 Rgenix, Inc. Inhibitors of creatine transport and uses thereof
US10717704B2 (en) 2014-04-30 2020-07-21 Rgenix, Inc. Inhibitors of creatine transport and uses thereof
EP3950673A1 (fr) * 2014-04-30 2022-02-09 Inspirna, Inc. Inhibiteurs de transport de créatine et leurs utilisations
US12011427B2 (en) 2019-12-11 2024-06-18 Inspirna, Inc. Methods of treating cancer
CN116283632A (zh) * 2023-02-24 2023-06-23 吉首大学 一类β-氨基-α-卤代/硒代羧酸酯及其合成方法和用途
CN117164483A (zh) * 2023-09-07 2023-12-05 吉尔生化（上海）有限公司 一种Cbz-精氨酸叔丁酯的合成方法

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